NE2201: Mycobacterial Diseases of Animals

(Multistate Research Project)

Status: Active

NE2201: Mycobacterial Diseases of Animals

Duration: 10/01/2022 to 09/30/2027

Administrative Advisor(s):


NIFA Reps:


Statement of Issues and Justification

The proposed multi-state initiative will focus on two of the most important mycobacterial diseases affecting animals; paratuberculosis (Johne’s disease; JD) and the Mycobacterium tuberculosis complex (TB). These two mycobacterial diseases represent some of the most prevalent and economically significant infections of livestock, and each has a long and rich history. A brief background, including significance and need for work, on each of these diseases, is provided below.

Johne’s Disease (JD) is a chronic granulomatous inflammatory intestinal disease that results from infection with Mycobacterium avium subspecies paratuberculosis (MAP). JD is recognized as a serious economic and animal health issue in domesticated ruminants including dairy and beef cattle, sheep, and goats throughout the world. The disease results in more than $200 million of annual losses to the United States (US) dairy industry each year, with additional losses incurred by the other species. Additionally, recent evidence of the presence of M. paratuberculosis in retail milk sources has led to concern about milk quality. The growing recognition of MAP infection in wildlife species and their living environments is also of considerable concern, with contaminations being found within abiotic factors that affect us all, such as grassland, soil, and water-supply systems. Despite considerable efforts, JD remains a major concern for producers, having very high prevalence rates (68% of all US dairy herds and 95% of those with over 500 cows have at least one JD positive animal) based on culturing of fecal samples. MAP and JD are now considered endemic in the US and in most dairy producing nations, and without major breakthroughs, efforts at controlling the pathogens are likely to remain salutary and the disease will continue to spread unabated.

Considerable ongoing efforts have been and are being made to identify knowledge gaps, define research priorities, and develop recommendations for implementing JD control measures in the field. For instance, a 2003 report from the National Research Council of the US National Academies of Sciences on JD comprehensively reviewed the literature, identified major gaps in knowledge, and provided clear recommendations for future research priorities and strategies for the prevention and control of JD. In brief, the report concluded that JD is a significant animal health problem whose study and control deserves high priority from the USDA. It was recognized that the problems associated with JD stem from: (i) difficulties in diagnosis because of an unusually long incubation period and a lack of specific and sensitive diagnostic tests for detecting early infections; (ii) a lack of vaccines or other effective measures for infection control; and (iii) general lack of awareness of the disease and its true economic and animal health consequences by producers and veterinarians. The report made 25 specific recommendations including: implementation of strategies for the control of JD, educating and training of producers and veterinarians, and filling of key gaps in knowledge relating to JD. In 2005 and 2006, the USDA-APHIS-VS and the Johne’s Disease Integrated Program (JDIP; http://mycobacterialdiseases.org/) formulated specialty working groups to review knowledge gaps and opportunities for research, extension, and training in JD.

The specialty working groups identified the following community needs: (i) the development of new and improved diagnostics and candidate vaccines; (ii) improvement of research efficiencies by developing shared resources and guidelines for basic and translational research in JD; and (iii) development of strong education and extension programs. While considerable progress has been made in all areas, the proposed multi-state initiative is necessary to fulfill the remaining unmet needs.

The mycobacterium tuberculosis complex is a group of genetically related bacterial species that cause tuberculosis infection in humans and animals. Tuberculosis infection in livestock results mostly from the specific mycobacterium pathogens of M. bovis and Mycobacterium avium subspecies avium (MAA). These organisms can cause disease in multiple livestock and wild animal species and can be readily transmitted to humans. M. bovis, whose disease and infections will be the primary focus of the activities proposed in this multi-state initiative, is closely related to the organism that causes human tuberculosis, Mycobacterium tuberculosis (MTB).

TB is a disease of antiquity that has resulted in considerable economic losses to animal agriculture and, as a zoonotic disease, contributed greatly to human suffering prior to the widespread requirement for milk pasteurization. In fact, at the turn of the 20th century, M. bovis was considered to be the cause of greater economic losses in livestock production than all other infectious diseases combined. The implementation of rigorous control and disease eradication programs, including test and slaughter or test and segregate programs, have reduced or eliminated tuberculosis in cattle in the US and most developed countries. However, reservoirs in wildlife have precluded complete eradication. TB continues to be a significant recurring concern in many countries, including Ireland, the United Kingdom (UK) and New Zealand. In addition, both bovine tuberculosis and M. bovis infections in humans remain common in less developed countries, resulting in considerable economic losses due to disease and trade restrictions.

While TB incidence in the US remains low, there is considerable concern that we may be experiencing a resurgence of this disease in livestock and wildlife species. In 1994, a white-tailed deer (WT deer) from northeastern Michigan was found to be infected with M. bovis. This led to the wide-scale testing of cattle and deer with subsequent identification of M. bovis in both populations within this area. The spread of M. bovis in Michigan was slowed by a strict policy of total herd depopulation upon identification of positive cattle, as well as large-scale hunter education programs and a massive testing initiative in WT deer. Still, in Michigan, over 650 cases of M. bovis infection in WT deer and 49 positive cattle herds have been identified to date. Alarmingly, M. bovis has now spread to other states. M. bovis was recently detected in 27 WT deer and 12 cattle herds in Minnesota and has been confirmed in cattle from Colorado, Nebraska, Indiana, Kentucky, North Dakota, South Dakota, New Mexico, and California. Detection of M. bovis infection has lead to quarantine and depopulation of all nearby affected herds. Clearly, this disease is continuing its resurgence throughout the US, particularly where cattle and WT deer commingle.

A second major source of M. bovis infected cattle in the US is imported animals from other countries where the disease is endemic, particularly Mexico. Indeed, molecular epidemiology studies have demonstrated that M. bovis cases in all states other than Michigan are likely of Mexican origin. Although USDA regulations stipulate that imported cattle must be tested within 60 days of import, the low sensitivity of most approved M. bovis diagnostic tests suggests that some infected animals will be missed. Since cattle are only held at the border for 48 to 72 hours, there is little time to conduct additional testing at the point of entry. In addition, the lack of mandatory animal identification in the US limits the ability to track cattle after they have entered the country. Clearly, it is crucial to have rapid diagnostics with improved sensitivity that could be deployed at points of entry. It is equally important to improve information on cattle movements after importation to track M. bovis infected cattle.


M. bovis is of significant concern to government agencies and cattle industries due to associated economic, social and potential public health problems. The inclusion of M. bovis research, teaching and extension in this multi-state project will address serious concerns from cattle industry representatives, government agencies, and public health officials. Their major concern is that the US is experiencing a resurgence of M. bovis that will have devastating economic effects, cause a disruption or severe restrictions in movements of cattle including exports, and have profound effects on producers, who own positive herds and must suffer depopulation or quarantine.

The generation of new knowledge relative to the diagnosis, management, and control of mycobacterial diseases of animals is critical if we are to prevent the spread, lower the prevalence and minimize the impact of the diseases in our livestock populations. USDA NAHMS studies and other work, including the National Dairy Producer Johne’s survey, have shown that while producers are increasingly aware of the diseases, they often lack knowledge relative to their management and control. Therefore, there is a critical need for developing coordinated approaches for education and outreach programs related to mycobacterial diseases of animals.

Taken together, the proposed multi-state initiative described below will facilitate the development of shared research as well as the leveraging of intellectual and physical resources to address some of the most important mycobacterial diseases of animals.

Related, Current and Previous Work

The proposed multi-state initiative will focus on two of the most important mycobacterial diseases of animals; paratuberculosis (Johne’s disease; JD) and the bovine tuberculosis complex (TB). These two mycobacterial diseases represent some of the most prevalent and economically significant infections of livestock, and each has a long and rich history. A brief background, including the significance and need for work, on each of these diseases is provided below. Johne’s Disease (JD) is a chronic granulomatous inflammatory intestinal disease that results from infection with Mycobacterium avium subspecies paratuberculosis. JD is recognized as a serious economic and animal health problem in domesticated ruminants including dairy and beef cattle, sheep, and goats throughout the world. It results in more than $200 million in annual losses to the United States (US) dairy industry each year with additional losses incurred by the other species. The growing recognition of M. paratuberculosis infection in wildlife species is also of considerable concern. Similarly, recent evidence of the presence ofM. paratuberculosis in retail milk sources is of concern from a milk quality and potential food safety standpoint. The growing recognition of MAP infection in wildlife species is also of considerable concern, as well as contaminations in environments such as grassland, soil, and even water-supply systems. Despite considerable efforts, JD remains a major concern for producers with very high prevalence rates (68% of all US dairy herds and 95% of those with over 500 cows have at least one JD positive animal) based on culturing of fecal samples. MAP and JD are now considered endemic in the US and in most dairy producing nations, and without major breakthroughs, efforts at controlling pathogen are likely to remain salutary and the disease will continue to spread unabated.

There have been considerable ongoing efforts made to identify knowledge gaps, define research priorities, and develop recommendations for implementing JD control measures in the field. For instance, a 2003 report from the National Research Council of the US National Academies of Sciences on JD comprehensively reviewed the literature, identified major gaps in knowledge, and provided clear recommendations for future research priorities and strategies for the prevention and control of JD. In brief, the report concluded that JD is a significant animal-health problem whose study and control deserve high priority from the USDA. It was recognized that the problems associated with JD stem from: (i) difficulties in diagnosis because of an unusually long incubation period and a lack of specific and sensitive diagnostic tests for detecting early infections; (ii) a lack of vaccines or other effective measures for infection control; and, (iii) general lack of awareness of the disease and its true economic and animal-health consequences by producers and veterinarians. The report made 25 specific recommendations regarding the implementation of strategies for the control of JD, educating and training of producers and veterinarians, and filling of key gaps in knowledge relating to JD. In 2005 and 2006, specialty-working groups were formulated by the USDA-APHIS-VS and the Johne’s Disease Integrated Program (JDIP; http://mycobacterialdiseases.org/) to review knowledge-gaps and opportunities for research, extension and training in JD.

 

Some of the community needs that were identified as gaps included: (i) the development of new and improved diagnostics and candidate vaccines; (ii) improving research efficiencies by developing shared resources and guidelines for basic and translational research in JD; and, (iii) developing strong education and extension programs. While considerable progress has been made in all areas, the proposed multi-state initiative will facilitate meeting remaining major unmet needs.

 

The TB complex of diseases of livestock results from infection of animals with mycobacterial pathogens, primarily M. bovis and Mycobacterium avium subspecies avium (MAA). These organisms can cause disease in multiple livestock and wild animal species and can be readily transmitted to humans. M. bovis, whose disease and infections will be the primary focus of the activities proposed in this multi-state initiative, is closely related to the organism that causes human tuberculosis, Mycobacterium tuberculosis (MTB).

 

TB is a disease of antiquity that has resulted in considerable economic loss to animal agriculture and, as a zoonotic disease, contributed greatly to human suffering prior to the widespread requirement for milk pasteurization. In fact, at the turn of the 20th century, M. bovis was considered to be the cause of greater economic losses to livestock production than all other infectious diseases combined. The implementation of rigorous control and disease eradication programs, including test and slaughter or test and segregate programs, have reduced or eliminated tuberculosis in cattle in the US and most developed countries. However, reservoirs in wildlife have precluded complete eradication. TB continues to be a significant recurring concern in many countries, including Ireland, the United Kingdom (UK) and New Zealand. In addition, both bovine tuberculosis and M. bovis infections in humans remain common in less developed countries, resulting in considerable economic losses due to disease and trade restrictions.

 

While TB incidence in the US remains low, there is considerable concern that we may be experiencing a resurgence of this disease in livestock species, primarily cattle. In 1994, a white-tailed deer (WT deer) from northeastern Michigan was found to be infected with M. bovis. This led to wide-scale testing of cattle and deer with subsequent identification ofM. bovis in both populations within this area. The spread of M. bovis in Michigan was slowed by a strict policy of total herd depopulation upon identification of positive cattle, as well as large-scale hunter education programs and a massive testing initiative in WT deer. Still, in Michigan, over 650 cases of M. bovis infection in WT deer and 49 positive cattle herds have been identified to date. Alarmingly, M. bovis has now spread to other states.M. bovis was recently detected in 27 WT deer and 12 cattle herds in Minnesota and has been confirmed in cattle from Colorado, Nebraska, Indiana, Kentucky, North Dakota, South Dakota, New Mexico, and California. Detection of M. bovis infection has lead to quarantine and depopulation of nearly all affected herds. Clearly, this disease is continuing its resurgence throughout the US, particularly where cattle and WT deer commingle.

 

A second major source of M. bovis infected cattle in the US is imported animals from other countries where the disease is endemic, particularly Mexico. Indeed, molecular epidemiology studies have demonstrated that M. bovis cases in all states other than Michigan are likely of Mexican origin. Although USDA regulations stipulate that imported cattle must be tested within 60 days of import, the low sensitivity of most approved M. bovis diagnostic tests suggests that some infected animals will be missed. Because cattle are only held at the border for 48 to 72 hours, there is little time to conduct additional testing at the point of entry. In addition, the lack of mandatory animal identification in the US limits the ability to track cattle after introduction into the country. Clearly, it is crucial to have rapid diagnostics with improved sensitivity that could be deployed at points of entry. It is equally important to improve information on cattle movements to control importation of M. bovis infected cattle.

 

  1. bovis is of significant concern to government agencies and cattle industries due to associated economic, social and potential public health problems. The inclusion of bovis research, teaching and extension in this multi-state project will address serious concerns from cattle industry representatives, government agencies, and public health officials that the US is experiencing a resurgence of M. bovis that will have devastating economic effects, cause a disruption or severe restrictions in movements of cattle including exports, and have profound effects on producers, who own positive herds and must suffer depopulation or quarantine.

 

Finally, the generation of new knowledge relative to the diagnosis, management and control of mycobacterial diseases of animals is critical if we are to prevent the spread, lower the prevalence and minimize the impact of the diseases in our livestock populations. USDA NAHMS studies and other work, including the National Dairy Producer Johne’s survey, have shown that while producers are increasingly aware of the diseases, they often lack knowledge relative to their management and control. Therefore, there is a critical need for developing coordinated approaches for education and outreach programs related to mycobacterial diseases of animals.

 

Taken together, the proposed multi-state initiative described below will facilitate the development of shared research as well as the leveraging of intellectual and physical resources to address some of the most important mycobacterial diseases of animals.

 

In terms of prior and current related work, during the fall of 2004, the USDA-CSREES-NRI’s Coordinated Agricultural Projects (CAP) helped bring together leading scientists in the field of JD to form a comprehensive, multi-institutional, interdisciplinary Johne’s Disease Integrated Program for research, education, and extension, or JDIP. We started with a team of approximately 70 scientists from two-dozen leading academic and government institutions in the US, who represented the diverse disciplines of microbiology, immunology, pathology, molecular and cellular biology, genomics, proteomics, epidemiology, clinical veterinary medicine, public health, extension, and public policy. Since its inception, membership in MDA has grown to more than 220, and the program has become international in scope.

 

Based on the success of the program, JDIP was renewed in 2008, and the Multistate Initiative program in the Mycobacterial Diseases of Animals-Multistate initiatives enabled JD research, education, and extension to rapidly move forward in a manner that would not be possible through traditional funding mechanisms from the USDA. In particular, the founding and continued support of MDA has enabled the community, for the first time since JD was described more than a century ago, to develop an integrated and coordinated program with a focus on developing a strong translational pipeline of new diagnostic tests, vaccine candidates, strategies to manage, prevent and control the disease, and the formulation of an outstanding education and training program. As detailed in the sections below, in the brief period since the founding of the program, JDIP investigators have conducted path-breaking research and development that has resulted in:

 

A better understanding of paratuberculosis on-farm transmission dynamics that is helping identify critical control points in the transmission chain.

The development of alternative sampling and testing strategies for detection of infected animals and herds that are being adopted by the national voluntary control program for JD.

The optimization and standardization of laboratory protocols for paratuberculosis culture and PCR for reducing timelines for rapid and sensitive detection of infected animals.

Characterization of genetic differences between isolates ofparatuberculosis for molecular epidemiologic analyses and tracking of strains in infected animals and the environment.

Development of standards for animal challenge models withparatuberculosis for the evaluation of vaccine efficacy. Identification of key genes, proteins and lipids unique toparatuberculosis for development of the next generation of diagnostic tests and vaccines.

Development and widespread use of an on-line JD veterinary certification program.

Development of educational modules for producers as well as field and laboratory technicians providing milk ELISA tests for producers.

Development of community resources including paratuberculosis isolates, serum samples and other clinical material for the development and validation of diagnostic tests, genomic microarrays, recombinant proteins, and mutant strain banks of M. paratuberculosis for identification of potential vaccine candidates.

Development an individual-based dairy herd model by incorporating basic herd dynamics in a closed herd environment where no new animals have been bought from outside.

Development of a useful platform for gene discovery and analysis by isolating three novel mutants for each transposon. Establishment of high quality longitudinal data collection which turned out to be an essential tool in our understanding of pathobiology and epidemiology of MAP infections in dairy herds

Development of a peptide-based vaccine for cattle using the PLGA NP delivery systems

Evaluation of the Bovine Leukemia Virus and Mycobacterium avium subsp. paratuberculosis relationship with Shiga Toxin-Producing Escherichia coli Shedding in Cattle

Evaluation of the humoral immunity and atypical cell-mediated immunity in response to vaccination in cows naturally infected with bovine leukemia virus

Screen the bovine serum samples with MTB and MAP protein microarray for antigen discovery

Research on the evaluation of prevention of infection by stimulating innate response usingMycobacterium bovis as the model of infection.

Establishment of model systems that can be used to obtain crucial information that would unveil key aspects of MAP pathogenesis, and would enable the researchers to compare the different phases of the disease between in vitro and in vivo systems.

Determining the role of luxR homolog gene in invasion of MAP into epithelial cells usingMycobacterium smegmatis as a model of infection.

Investigation of the phenotypic diversity in the immune response againstMycobacterium avium paratuberculosis in MAP- infected dairy cows.

Identification of several candidate MAP proteins of potential utility for the early detection of MAP infection. Detection of pathogens and control pathogen transmission, both within-herd transmission and between-herd transmission.

Development of a quantitative methodology for incorporating whole genome sequence (WGS) data into bacterial transmission models for infectious diseases incorporating ecology, economics, molecular biology, and epidemiology. Better understanding of the principles and dynamics governing transmission of mycobacterial infection.

Development, assessment, and implementation of vaccines for JD and bTB.

Providing veterinarians, producers of potentially impacted species, state and federal policy makers, and other stakeholders with accurate, high quality, up to date, and easy to access information and education to assist efforts that will effectively address mycobacterial diseases.

 

 

In addition to our research accomplishments, we have developed a strong communications and extension plan that includes workshops, newsletters, regular conference calls, and an annual conference of JD researchers. Hence, MDA has brought together scientists and stakeholders with a shared vision and well-defined plan to support and facilitate research, extension and education activities and enhance animal health through biosecurity by addressing well-documented and emerging needs in JD.

 

Workshop on Accelerating bovine Tuberculosis (bTB) Control in Developing Countries

 

With funding from Bill & Melinda Gates Foundation, The University of Georgia, Cornell University, and The

 

Pennsylvania State University, a Workshop on Accelerating bovine Tuberculosis (bTB) Control in Developing Countries was conducted on December 8-10, 2015 in Rabat, Morocco. The workshop was a representation of the collective efforts of a committed and diverse global group of bTB experts who convened to develop a shared vision and forward-looking research agenda for developing and implementing effective bTB control strategies in developing countries.

 

The workshop was co-chaired by Vivek Kapur (Penn State, US), Martin Vodermeier (Animal and Plant Health Agency, UK), Yrjo Grohn (Cornell, US), and Fred Quinn (UGA, US). The workshop brought together a diverse group of 40 leading bTB investigators from 16 countries, which worked with policy makers and funding agency representatives to develop a shared vision and strategic framework for the implementation of bTB control programs in developing countries in which the disease is endemic in livestock, humans, and wildlife.

 

Participant presentations and discussions provided key insights on seven topical areas including: (1) vaccines and diagnostics, (2) the zoonotic impact of bTB, (3) bTB control efforts that have worked to date, (4) the World Organization for Animal Health (OIE) perspective, (5) the African perspective, (6) implications of bTB in wildlife, and (7) the India and China perspectives. Participants generated an initial 175 insights and 154 questions through discussions, and an “idea sorting” round-robin exercise worked to enhance the robustness of the knowledge base and identify the top five most critical insights and questions for each topic area. The group developed an integrated strategy map and detailed five-year action plan to help meet these three key inter-dependent and inter-related needs: (i) Establishment of the business case through rigorous bTB risk and economic impact assessments and the development of advocacy tools for bTB control programs, (ii) Establishment of technical capabilities to ensure the widespread availability of and access to fit-for purpose diagnostic tests and vaccines, (iii) Establishment of key market and public investment operational drivers and the creation of value-chain for bTB control by small- holder farmers.

 Hence, the renewed multi-state proposal seeks to continue to build the considerable progress we have made during the past two phases of JDIP so that we can continue to leverage the financial and scientific resources even after the completion of the second Phase of the program. We are convinced that the accomplishments of this CAP project thus far have created a momentum that will continue to grow through the proposed multi-state initiative that expands the focus from JD to include TB and mycobacterial diseases in animals.

Objectives

  1. Objective 1 will focus on understanding the epidemiology and transmission of JD and TB in animals through the application of predictive modeling and assessment of recommended control practices. Comments: To accomplish our overall objective of developing a better understanding of the epidemiology and transmission of JD and TB.
  2. Objective 2 will seek to develop and implement new generations of diagnostic tests for JD and TB. Comments: Improved methods for the rapid, specific, sensitive, and cost-efficient diagnosis of JD or TB-infected remain a major priority.
  3. Objective 3 will focus on improving our understanding of biology and pathogenesis of Mycobacterial diseases, as well as the host response to infection
    Comments: It is well recognized that the ability to identify the route of invasion and the host-pathogen interactions at a molecular level is important for the future development of strategies to prevent infections or to limit the spread of the infection. Similarly, the elucidation of gene products specific to in vivo growth holds great promise in identifying new antigens for diagnostics or vaccine development, as well as products essential to pathogenesis. Hence, as part of the proposed multi-state initiative, we envision studies of the basic biology of the causative organisms of JD and TB and their interaction with the host. Specifically, we anticipate studies that will employ state-of-the-art microbiological, molecular biology, genomic, proteomic, metabolomic, immunology, and or bioinformatic approaches.
  4. Objective 4 will focus on development of programs to create and evaluate and develop new generations of vaccines for JD and TB.
    Comments: Under the auspices of this multi-state initiative, we propose specific research projects to help achieve each of the 4 objectives and include a strong education and extension plan. We envision many of the projects to be crosscutting in nature (i.e. cut across objectives and/or address both diseases) that will together help address the major animal, human, and societal issues surrounding detection and control of mycobacterial diseases in animals. It is important to note that our research objectives are closely linked and coordinated with our education, extension and outreach plan.

Methods

Objective 1 will focus on understanding the epidemiology and transmission of Mycobacterial diseases in animals. To accomplish our overall objective of developing a better understanding of the epidemiology and transmission of JD and TB, we propose studies that include:

Continued development of mathematical models of JD and TB transmission dynamics, including within-host, between individuals, within and between domesticated dairy and beef herds and wildlife, as well as on an ecological scale. For example, several investigators have initiated the process of development of mathematical models for JD and TB (2-4) and we will continue the process with studies such as estimating the performance of JD vaccines, defining the impact of wildlife infection on JD and TB dynamics, analyzing the spread of JD and TB through cattle trading networks, and finding economically optimal JD and TB control strategies. Examples of the types of investigations that will be carried out are presented in(5-7).

Characterization of herd and environmental distribution of specific genotypes ofparatuberculosis and M. bovis using state-of-the-art methods for strain differentiation using simple sequence repeats and or single nucleotide-based typing approaches and applying this knowledge to characterize the genetic diversity and molecular epidemiology of M. paratuberculosis and M. bovis infections;

Delineation of mycobacterial disease transmission dynamics, including paratuberculosis transmission within calf-rearing systems, risk of M. paratuberculosis transmission from infected dams to daughters, and risk of M. paratuberculosis infection associated with ‘super-shedders’ and calf-to-calf transmission;

Clarification and delineation of critical management practices for control, prevention, and eradication of mycobacterial diseases; and,

Identification and optimization of surveillance methods and strategies.

 

Taken together, these studies will significantly advance our understanding of the epidemiology and transmission dynamics of mycobacterial diseases of animals.

 

Objective 2 will seek to develop and implement new generations of diagnostic tests for JD and TB. Improved methods for the rapid, specific, sensitive, and cost-efficient diagnosis of JD or TB infected remain a major priority. Hence, as part of this multi-state initiative, we anticipate carrying out investigations that include:

 

Development of methods for the early detection ofparatuberculosis and M. bovis infected animals, including newer generations of molecular, serological and microbiological assays with greater sensitivity, specificity, speed, and or ease- of-use, by using state-of-the art molecular biological, immunological, and materials science and engineering methods and approaches; and,

Development of resources for validation and standardization of diagnostic assays, including well-accessioned biological sample collections (strains, tissue, clinical samples, etc.), and processes to make these accessible to the scientific community.

 

Together, these studies and efforts will facilitate the development, validation, and implementation of the next-generation of improved diagnostic tests for mycobacterial diseases of animals.

 

Objective 3 will focus on improving our understanding of biology and pathogenesis of Mycobacterial diseases of animals, as well as the host response to infection. Our understanding of the basic biology and mechanisms of pathogenesis of

  1. paratuberculosis and M. bovis is far from complete. It is well recognized that the ability to identify the route of invasion and the host-pathogen interactions at a molecular level is important for the future development of strategies to prevent infections or to limit the spread of the infection. Similarly, the elucidation of gene products specific to in vivo growth holds great promise in identifying new antigens for diagnostics or vaccine development, as well as products essential to pathogenesis.

 

Hence, as part of the proposed multi-state initiative, we envision studies of the basic biology of the causative organisms of JD and TB and their interaction with the host. Specifically, we anticipate studies that will employ state-of-the art microbiological, molecular biology, genomic, proteomic, metabolomic, immunology, and or bioinformatic approaches to carry out studies that include:

 

Investigations into the basic mechanisms of pathogen invasion of host cells and tissue using state-of the art methods in mycobacteriology, cell biology, and genomics;

Identification of mycobacterial genes and proteins whose inactivation or alternated expression results in reduced virulence. This will be accomplished by screening large libraries of mutants, as well as by characterizing these mutant strains using state-of-the art genomics and proteomics based methods and will also lead to the identification of genes associated with the ability of the pathogen to survive in the host as markers for virulence and pathogenicity; and, Characterization of the microbial factors that contribute to the innate and adaptive immune response using sophisticated in vitro cellular immunologic assays and animal models of infection.

Exploitation of knowledge from immune response studies to create new methods of diagnosis.

 

Taken together, we anticipate that these investigations will reveal important insights on the basic biology of the causative organisms of JD and TB and their interaction with their hosts.

Objective 4 will focus on the evaluation and development of new generations of vaccines for JD and TB.It is well recognized that defining the host genetic, cellular and molecular events associated with susceptibility to JD and TB is essential for the development of candidate vaccines and host genetic selection for resistance. For TB in particular, the experience in the UK and elsewhere have shown that traditional test/slaughter and abattoir inspection campaigns fail to control the spread of bovine TB (bTB), most likely due to the presence of a wildlife reservoir. Vaccine research must become a priority. Similarly, in the US where a wildlife reservoir exists, control efforts have not eradicated bTB and are unlikely to do so. Hence, the development of a vaccine against bTB is required to control disease. Under the auspices of this multi-state initiative, we envision projects that will seek to develop candidate vaccines, identify genes and markers associated with susceptibility of animals to mycobacterial infection, and define the cellular and molecular events associated with development of immune responses to M. paratuberculosis and M. bovis in cattle. Specifically, we anticipate the development of projects that will:

 

Analyze the early immune response to infection as well as the host response to animals at different stages of disease using well-characterized in vitro models and animal experimentation;

Develop and validate animal models for vaccine development;

Identify genetic markers for susceptibility to infection in cattle using genome wide association studies with well-defined resource populations. A combination of candidate gene identification with whole genome SNP typing promises to rapidly identify a set of markers that could be used to select for resistance to disease caused by mycobacteria;

Compare the efficacy of candidate vaccines in animal models of infection. We hypothesize that live attenuated vaccines are likely to elicit a protective response superior to the response elicited by currently available killed vaccines. However, it will be essential to develop vaccine candidates that are able to differentiate vaccinated from naturally infected animals.

To test this hypothesis, we anticipate studies that include: (a) use of flow cytometry, long-oligo microarrays, and real time RT-PCR to compare immune responses elicited by candidate mutant vaccines; (b) Determine if mutant vaccines elicit development of effector memory CD4 and/or CD8 T cells that kill infected autologous macrophages or arrest replication of intracellular bacteria; and, (c) Determine if animal immunized with mutant vaccines are protected against challenge; Evaluate the ability of recombinant or vector expressed proteins and mycobacterial lipids to elicit effector T cells with the capacity to kill infected macrophages or arrest replication of intracellular bacteria. The working hypothesis is that modification of mycobacterial antigens by attachment of Trojan peptides will selectively enhance development of long- lived memory CD4 and/or CD8 effector T cells and may be suitable candidate antigens for use as subunit vaccines; and, Determine the role of regulatory T cells in the immunopathogenesis of mycobacterial infections in animals. The working hypothesis is that dysregulation of the immune response to paratuberculosis and M. bovis is, at least in part, attributable to development of regulatory T cells (Tregs). Evidence suggests that Tregs may be responsible for down-regulating effector memory CD4 cells in an antigen-specific manner. This hypothesis will be tested by characterizing cell surface markers of Tregs using flow-cytometeric and expression analysis techniques.

 Taken together, we anticipate that these investigations will reveal important insights into the immune response of animals to mycobacterial infections, as well as lead to the identification and evaluation of candidate vaccines.

Measurement of Progress and Results

Outputs

  • Research data, methods Comments: The outputs, including research data, methods Comments: a. A better understanding of the epidemiology and transmission of JD and TB in animals, and the development of predictive models of infection; b. New generations of diagnostic tests for JD and TB that are sensitive, specific, rapid, and cost-efficient; c. Improved understanding of the biology and pathogenesis of mycobacterial diseases of animals, as well as the host response to infection; d. Development and evaluation of new generations of vaccines for JD and TB; e. Development of shared resources and protocols; and, f. Development of education materials and delivery plan to provide veterinarians, producers of potentially impacted species, state and federal policy makers and other stakeholders with accurate, high quality, up to date, and easy to access information related to mycobacterial diseases of animals.

Outcomes or Projected Impacts

  • Outreach Plan We recognize and appreciate that outreach and education efforts are vital components in achieving the objectives of this multi- state initiative, as described above. The underlying mission of our outreach plan is to provide veterinarians, producers of potentially impacted species, state and federal policy makers, and other stakeholders with accurate, high quality, up to date, and easy to access information and education to assist efforts that will effectively address mycobacterial diseases. To accomplish this, we need to better understand the factors that encourage or deter veterinarians and their producer clients from adopting JD and TB control or eradication practices, as well as the educational needs of these populations, to develop educational materials based on current, evidence-based information and deliver these materials in a flexible, convenient, cost- effective, and readily available manner.
  • objectives for the education and outreach component of this multi-state initiative Create an internet portal to provide access to information related to mycobacterial diseases, specifically JD and bTB. Internet access provides the most rapid, cost effective means to sharing information with a widely distributed audience. The site will provide convenient access to information generated through the initiative and seek to be as comprehensive as possible by sharing previously developed information through links to existing sites such as jdip.org, www.johnes.org, and www.johnesdisease.org. Links to international sites will allow US scientists, producers, and policy makers access to information on the success of domestic herd and wildlife control programs, such as the badger vaccination program in Ireland. These sites already exist and are supported from various extramural and intramural sources, and we anticipate that we will continue to seek funding for the development, management, and curation of these web-sites. Encourage, monitor and increase awareness of the publication of work of initiative collaborators in peer-reviewed journals and through other scientific outlets. Publication of research results in peer reviewed journals is important to the initiative and to those who collaborate in the effort, since it validates the credibility of the work and makes it more widely available. The Education/Outreach team will strongly encourage publication of initiative research in appropriate journals. We will seek to make others in the industry aware of work as it is published and also monitor the publications for work that may be shared with producers and others through the initiative. Current Johne’s efforts have developed a strong international network of scientists and interested professionals, through the International Association for Paratuberculosis (IAP), who are effectively sharing information as they work to address this world-wide disease. Efforts in other nations are also looking to address a wider range of mycobacterial diseases, so this initiative will fit well into expanding international efforts. We will seek to maintain and enhance current working relationships and explore new ones that will allow the most effective use of existing resources. Enhance and strengthen working relationships and communication links with producer and professional organizations. While many good working relationships currently exist, expanding these networks will increase awareness of the initiative, build confidence in the results and help to make them more readily available to our target audiences.
  • Activities to reach our goals 1. Partnering with the Animal Health committee for the Joint Annual Meeting (JAM) of the American Dairy Science Association and the American Society of Animal Science to include specific oral and poster presentation sections for mycobacterial diseases at the JAM. Include, as appropriate, mycobacterial sessions/symposia in the scientific sessions of the American Association of Bovine Practitioners (AABP), the Association of Veterinary Consultants (AVC) and the American Veterinary Medical Association (AVMA). This will provide an opportunity to reach large and very important target audiences in a cost effective manner. It will also assure inclusion of abstracts of the work presented in highly respected journals that are readily available nationally and internationally. 2. Holding “Interest Group” meetings at the JAM, the annual meeting of the American Association of Bovine Practitioners (AABP), the Association of Veterinary Consultants (AVC) and similar meetings to reach extension and industry professionals with interests in this area by providing them with information from the initiative, seeking input on current and planned activities, and inviting their participation in the initiative. 3. Coordinate preconference seminars, or clinical forums, on a periodic basis at the annual conference of the AABP to reach professionals who are on the farm with timely information and solicit their input on additional needs that the initiative is equipped to address. 4. Facilitate discussion with government and industry to consider expansion of the National Johne’s Work Group (NJWG), currently a subcommittee of the US Animal Health Association (USAHA)’s Johne’s Disease Committee, to become a Mycobacterial Disease Work Group, working with the Tuberculosis and other appropriate USAHA committees. It is anticipated that this group would meet annually at the USAHA’s annual meeting and “as needed” at the annual meeting of the National Institute for Animal Agriculture (NIAA) to share information and identify additional research and education needs. 5. Partner with relevant organizations in organizing scientific and educational information sessions for producers focused on relevant topics. Potential collaborators include: 1. NCBA Cattlemen’s College 2. National Dairy Herd Information Association (NDHIA)
  • Joined Efforts World Dairy Expo 1. The Joint Annual Meeting of the National Milk Producers Federation (NMPF), the National Dairy Board (NDB) and the United Dairy Industry Association (UDIA) 2. Dairy and beef breed associations 3. The American Farm Bureau Federation (AFBF) 1. Partner with USDA to assist in training programs on related diseases 2. Organize, with industry, extension, and government agency collaboration, a national symposium on mycobacterial diseases of animals every five years 3. Develop and conduct webinar’s on “high interest” topics in conjunction with extension and or other industry partners Provide convenient access to comprehensive, high quality, and consistent education materials for veterinarians, producers and others. We will seek out and use existing tools, such as those currently available at http://ce.vetmed.wisc.edu/Johnes_Disease,that are developed and reviewed by experts in the field. Additional information that is needed will be identified and resources/collaborators needed to produce and deliver the material will be identified. Materials will be delivered electronically, but will include supporting material that can be printed locally. Leverage existing information/education delivery mechanisms to more comprehensively reach target audiences with information about mycobacterial diseases. We will work actively with trade media and partner with groups like the Johne’s Education Initiative (JEI), DAIReXNET, the eXtension Wildlife Damage Management Community of Practice, and the Internet Center for Wildlife Damage Management (ICWDM) in this effort. Reach non-traditional audiences, including policy makers and interested members of the public, with accurate and timely information relative to mycobacterial diseases in livestock and serve as a point of contact for further information needs. Social media tools such as “Linked In” and “Facebook” will be used to reach these audiences. We will seek to partner with and draw on expertise from industry groups to make the most effective use of these tools in a timely manner as this effort moves forward. ICP – Coauthored presentation on JD programs in the U.S. 2016 JAM Annual Meeting – MDA interest session, material available in press room and registration World Dairy Expo – met with 10 dairy trade publications, material available USAHA – Display and presentations to JD Committee, State, extension and Federal vets

Milestones

(0):We anticipate the following programmatic milestones. A) Each of the four objectives and the outreach and education plan will start during year 1 and continue through the duration of the project. B) An annual meeting of investigators. C) During year 3, working in concert with our stakeholders, we anticipate carrying out a needs assessment for both the research and outreach components of the program. D) Year 4 will involve a comprehensive evaluation of progress of the multi-state initiative, and focus on developing renewal applications.

Projected Participation

View Appendix E: Participation

Outreach Plan

Organization/Governance

Taken together, the above approach will help us achieve our objectives of providing veterinarians, producers, and other stakeholders with high-quality, up-to-date information and education to foster a cost-effective approach of managing JD and TB risk and preventing and controlling mycobacterial diseases in animals.


Organization/Governance

We build on our experience with the JDIP and TB-CAP initiatives and have formulated a robust plan for the administration of the multi-state initiative.

 

In brief, we have proposed the formation of an Executive Committee that will be responsible for all strategic, scientific, and management policy decisions for this multi-state initiative, and serve to advise the Administrative Advisor of the program. The Chair of the Executive Committee is responsible for the implementation and facilitation of programmatic goals and will serve as the primary liaison with the USDA, Experiment Station Directors, and external stakeholders. We also propose the formulation of an External Advisory Board, which will consist of public and private stakeholders (regulatory agencies, members of industry, and prominent scientists from related disciplines and Experiment Station Directors), to provide advice on programmatic matters, and ensure that the initiative stays true to its mission. The Chair of the External Advisory Board will be a member of the Executive Committee. The composition, membership and voting structure of the Executive Committee is described below:

 

Executive Committee. The initial Executive Committee will be comprised of a total of nine members, representing individuals with leadership in Mycobacterial disease research, extension, and education, a documented commitment to helping the community realize a shared vision, and a history of working together as a team. The proposed members of the Executive Committee are:

 

  • John Bannantine (National Animal Disease Center, USDA-ARS).
  • Luiz Bermudez (Oregon State University, OR).
  • Paul Coussens (Michigan State University, MI).
  • Yrjö Gröhn (Cornell University, NY).
  • Vivek Kapur (Penn State, PA). Initial Chair of the multi-state initiative.
  • Don Lein. (Cornell University, NY). Initial Chair of the External Advisory Board.
  • Kenneth Olson (KEO Consulting, IL).
  • Scott Wells (University of Minnesota, MN).
  • Rebecca Smith (Cornell University, NY).

 Governance of the Executive Committee:

 Chair: The chair of the committee is responsible for organizing the meeting agenda, conducting the meeting, and assuring those task assignments are The chair will be elected for at least a two-year term to provide continuity and be eligible for reelection.

 

  1. Chair-elect: The chair-elect will succeed the chair, and is expected to support the chair by carrying out duties assigned by the chair-elect and serves as the chair in the absence of the elected chair. Normally the chair-elect is elected for at least two years and be eligible for reelection.

 

  1. Secretary: The secretary is responsible for the distribution of documents prior to the meeting and is responsible for keeping the minutes, and preparing the accomplishments report (i.e., the SAES-422). The secretary will succeed the chair-elect and be eligible for
  2. Responsibilities of the Executive The Executive Committee is responsible for the overall management and administration of the program and will make all responsible efforts to achieve unanimous consent or make decisions through a simple majority vote. The executive committee may appoint sub-committees (that may comprise of any member of the multi-state initiative) whenever needed in order to make flexible and informed decisions and provide guidance to the program chair and executive committee and will nominate and vote on the composition of the external advisory board.

 

Program Members: In addition to carrying out the agreed research collaboration, research coordination, information exchange, or advisory activities, project members are responsible for reporting progress, contributing to the ongoing progress of the activity, and communicating their accomplishments to the committee’s members and their respective employing institutions.

 

Literature Cited

TB Publications: 2018-2021

 

Objective 1: Epidemiology

 

  • Avila LN, Goncalves VSP, Perez AM. Risk of Introduction of Bovine Tuberculosis (TB) Into TB-Free Herds in Southern Bahia, Brazil, Associated With Movement of Live Cattle. Front Vet Sci. 2018;5:230; doi: 10.3389/fvets.2018.00230.
  • Barandiaran S, Marfil MJ, Capobianco G, Perez Aguirreburualde MS, Zumarraga MJ, Eirin ME, et al. Epidemiology of Pig Tuberculosis in Argentina. Front Vet Sci. 2021;8:693082; doi: 10.3389/fvets.2021.693082.
  • Barandiaran S, Perez Aguirreburualde MS, Marfil MJ, Martinez Vivot M, Aznar N, Zumarraga M, et al. Bayesian Assessment of the Accuracy of a PCR-Based Rapid Diagnostic Test for Bovine Tuberculosis in Swine. Front Vet Sci. 2019;6:204; doi: 10.3389/fvets.2019.00204.
  • Cardenas NC, Pozo P, Lopes FPN, Grisi-Filho JHH, Alvarez J. Use of Network Analysis and Spread Models to Target Control Actions for Bovine Tuberculosis in a State from Brazil. Microorganisms. 2021;9(2); doi: 10.3390/microorganisms9020227.
  • Carneiro PA, Zimpel CK, Pasquatti TN, Silva-Pereira TT, Takatani H, Silva C, et al. Genetic Diversity and Potential Paths of Transmission of Mycobacterium bovis in the Amazon: The Discovery of M. bovis Lineage Lb1 Circulating in South America. Front Vet Sci. 2021;8:630989; doi: 10.3389/fvets.2021.630989.
  • Carneiro PAM, Takatani H, Pasquatti TN, Silva C, Norby B, Wilkins MJ, et al. Epidemiological Study of Mycobacterium bovis Infection in Buffalo and Cattle in Amazonas, Brazil. Front Vet Sci. 2019;6:434; doi: 10.3389/fvets.2019.00434.
  • de la Cruz ML, Pozo P, Grau A, Nacar J, Bezos J, Perez A, et al. Assessment of the sensitivity of the bovine tuberculosis eradication program in a high prevalence region of Spain using scenario tree modeling. Prev Vet Med. 2019;173:104800; doi: 10.1016/j.prevetmed.2019.104800.
  • Duffy SC, Srinivasan S, Schilling MA, Stuber T, Danchuk SN, Michael JS, et al. Reconsidering Mycobacterium bovis as a proxy for zoonotic tuberculosis: a molecular epidemiological surveillance study. Lancet Microbe. 2020;1(2):e66-e73; doi: 10.1016/S2666-5247(20)30038-0.
  • Hadi SA, Brenner EP, Mani R, Palmer MV, Thacker T, Sreevatsan S. Genome Sequences of Mycobacterium tuberculosis Biovar bovis Strains Ravenel and 10-7428. Microbiol Resour Announc. 2021;10(24):e0041121; doi: 10.1128/MRA.00411-21.
  • Islam SKS, Rumi TB, Kabir SML, van der Zanden AGM, Kapur V, Rahman A, et al. Bovine tuberculosis prevalence and risk factors in selected districts of Bangladesh. PLoS One. 2020;15(11):e0241717; doi: 10.1371/journal.pone.0241717.
  • Kakaire, R., N. Kiwanuka, S. Zalwango, J.N. Sekandi, T.H.T. Quach, M.E. Castellanos, F. Quinn, and C.C. 2020. Whalen. Excess risk of tuberculous infection among extra-household contacts of tuberculosis cases in an African city. Clin Infect Dis. Oct 16:ciaa1556.
  • Kanankege KST, Alvarez J, Zhang L, Perez AM. An Introductory Framework for Choosing Spatiotemporal Analytical Tools in Population-Level Eco-Epidemiological Research. Front Vet Sci. 2020;7:339; doi: 10.3389/fvets.2020.00339.
  • Kao SZ, VanderWaal K, Enns EA, Craft ME, Alvarez J, Picasso C, et al. Modeling cost-effectiveness of risk-based bovine tuberculosis surveillance in Minnesota. Prev Vet Med. 2018;159:1-11; doi: 10.1016/j.prevetmed.2018.08.011.
  • Lombard JE, Patton EA, Gibbons-Burgener SN, Klos RF, Tans-Kersten JL, Carlson BW, et al. Human-to-Cattle Mycobacterium tuberculosis Complex Transmission in the United States. Front Vet Sci. 2021;8:691192; doi: 10.3389/fvets.2021.691192.
  • Martinez, L., Y. Shen, A. Handel, S. Chakraburty, C.M. Stein, L.L. Malone, W.H. Boom, D. Quinn, M.L. Joloba, C.C. Whalen and S. Zalwango. Effectiveness of WHO's pragmatic screening algorithm for child contacts of tuberculosis cases in resource-constrained settings: a prospective cohort study in Uganda. 2018. Lancet Respir Med. 6(4):276-286.
  • Paudel S, Brenner EP, Hadi SA, Suzuki Y, Nakajima C, Tsubota T, et al. Genome Sequences of Two Mycobacterium tuberculosis Isolates from Asian Elephants in Nepal. Microbiol Resour Announc. 2021;10(36):e0061421; doi: 10.1128/MRA.00614-21.
  • Paudel S, Sreevatsan S. Tuberculosis in elephants: Origins and evidence of interspecies transmission. Tuberculosis (Edinb). 2020;123:101962; doi: 10.1016/j.tube.2020.101962.
  • Picasso-Risso C, Alvarez J, VanderWaal K, Kinsley A, Gil A, Wells SJ, et al. Modelling the effect of test-and-slaughter strategies to control bovine tuberculosis in endemic high prevalence herds. Transbound Emerg Dis. 2021;68(3):1205-15; doi: 10.1111/tbed.13774.
  • Picasso-Risso C, Perez A, Gil A, Nunez A, Salaberry X, Suanes A, et al. Modeling the Accuracy of Two in-vitro Bovine Tuberculosis Tests Using a Bayesian Approach. Front Vet Sci. 2019;6:261; doi: 10.3389/fvets.2019.00261.
  • Pozo P, Cardenas NC, Bezos J, Romero B, Grau A, Nacar J, et al. Evaluation of the performance of slaughterhouse surveillance for bovine tuberculosis detection in Castilla y Leon, Spain. Prev Vet Med. 2021;189:105307; doi: 10.1016/j.prevetmed.2021.105307.
  • Pozo P, Romero B, Bezos J, Grau A, Nacar J, Saez JL, et al. Evaluation of Risk Factors Associated With Herds With an Increased Duration of Bovine Tuberculosis Breakdowns in Castilla y Leon, Spain (2010-2017). Front Vet Sci. 2020;7:545328; doi: 10.3389/fvets.2020.545328.
  • Pozo P, VanderWaal K, Grau A, de la Cruz ML, Nacar J, Bezos J, et al. Analysis of the cattle movement network and its association with the risk of bovine tuberculosis at the farm level in Castilla y Leon, Spain. Transbound Emerg Dis. 2019;66(1):327-40; doi: 10.1111/tbed.13025.
  • Pullen MF, Boulware DR, Sreevatsan S, Bazira J. Tuberculosis at the animal-human interface in the Ugandan cattle corridor using a third-generation sequencing platform: a cross-sectional analysis study. BMJ Open. 2019;9(4):e024221; doi: 10.1136/bmjopen-2018-024221.
  • Rufai SB, McIntosh F, Poojary I, Chothe S, Sebastian A, Albert I, et al. Complete Genome Sequence of Mycobacterium orygis Strain 51145. Microbiol Resour Announc. 2021;10(1); doi: 10.1128/MRA.01279-20.
  • Salvador LCM, O'Brien DJ, Cosgrove MK, Stuber TP, Schooley AM, Crispell J, et al. Disease management at the wildlife-livestock interface: Using whole-genome sequencing to study the role of elk in Mycobacterium bovis transmission in Michigan, USA. Mol Ecol. 2019;28(9):2192-205; doi: 10.1111/mec.15061.
  • Singhla T, Boonyayatra S, Chulakasian S, Lukkana M, Alvarez J, Sreevatsan S, Wells SJ. 2019.  Determination of the sensitivity and specificity of bovine tuberculosis screening tests in dairy herds in Thailand using a Bayesian approach.  BMC Vet Res. 2019, May 16;15(1):149.
  • Srinivasan S, Easterling L, Rimal B, Niu XM, Conlan AJK, Dudas P, et al. Prevalence of Bovine Tuberculosis in India: A systematic review and meta-analysis. Transbound Emerg Dis. 2018;65(6):1627-40; doi: 10.1111/tbed.12915.
  • Verteramo Chiu LJ, Tauer LW, Smith RL, Grohn YT. Assessment of the bovine tuberculosis elimination protocol in the United States. J Dairy Sci. 2019;102(3):2384-400; doi: 10.3168/jds.2018-14990.
  • Wanzala SI, Nakavuma J, Travis D, Kia P, Ogwang S, Waters WR, et al. Retrospective Analysis of Archived Pyrazinamide Resistant Mycobacterium tuberculosis Complex Isolates from Uganda-Evidence of Interspecies Transmission. Microorganisms. 2019;7(8); doi: 10.3390/microorganisms7080221.

 

 

Objective 2: Diagnostics

 

  • Carneiro PAM, de Moura Sousa E, Viana RB, Monteiro BM, do Socorro Lima Kzam A, de Souza DC, et al. Study on supplemental test to improve the detection of bovine tuberculosis in individual animals and herds. BMC Vet Res. 2021;17(1):137; doi: 10.1186/s12917-021-02839-4.
  • de la Cruz ML, Branscum AJ, Nacar J, Pages E, Pozo P, Perez A, et al. Evaluation of the Performance of the IDvet IFN-Gamma Test for Diagnosis of Bovine Tuberculosis in Spain. Front Vet Sci. 2018;5:229; doi: 10.3389/fvets.2018.00229.
  • Duffy SC, Venkatesan M, Chothe S, Poojary I, Verghese VP, Kapur V, et al. Development of a Multiplex Real-Time PCR Assay for Mycobacterium bovis BCG and Validation in a Clinical Laboratory. Microbiol Spectr. 2021:e0109821; doi: 10.1128/Spectrum.01098-21.
  • Hadi SA, Waters WR, Palmer M, Lyashchenko KP, Sreevatsan S. Development of a Multidimensional Proteomic Approach to Detect Circulating Immune Complexes in Cattle Experimentally Infected With Mycobacterium bovis. Front Vet Sci. 2018;5:141; doi: 10.3389/fvets.2018.00141.
  • Kumar T, Singh M, Jangir BL, Arora D, Srinivasan S, Bidhan D, et al. A Defined Antigen Skin Test for Diagnosis of Bovine Tuberculosis in Domestic Water Buffaloes (Bubalus bubalis). Front Vet Sci. 2021;8:669898; doi: 10.3389/fvets.2021.669898.
  • Ortega J, Roy A, Alvarez J, Sanchez-Cesteros J, Romero B, Infantes-Lorenzo JA, et al. Effect of the Inoculation Site of Bovine and Avian Purified Protein Derivatives (PPDs) on the Performance of the Intradermal Tuberculin Test in Goats From Tuberculosis-Free and Infected Herds. Front Vet Sci. 2021;8:722825; doi: 10.3389/fvets.2021.722825.
  • Singhla T, Boonyayatra S, Chulakasian S, Lukkana M, Alvarez J, Sreevatsan S, et al. Determination of the sensitivity and specificity of bovine tuberculosis screening tests in dairy herds in Thailand using a Bayesian approach. BMC Vet Res. 2019;15(1):149; doi: 10.1186/s12917-019-1905-x.
  • Srinivasan S, Jones G, Veerasami M, Steinbach S, Holder T, Zewude A, et al. A defined antigen skin test for the diagnosis of bovine tuberculosis. Sci Adv. 2019;5(7):eaax4899; doi: 10.1126/sciadv.aax4899.
  • Srinivasan S, Subramanian S, Shankar Balakrishnan S, Ramaiyan Selvaraju K, Manomohan V, Selladurai S, et al. A Defined Antigen Skin Test That Enables Implementation of BCG Vaccination for Control of Bovine Tuberculosis: Proof of Concept. Front Vet Sci. 2020;7:391; doi: 10.3389/fvets.2020.00391.

 

Objective 3: Biology and Pathogenesis

 

  • Abreu R, L. Essler, A. Loy,  Quinn, and P. Giri. 2018. Heparin inhibits intracellular Mycobacterium tuberculosisbacterial replication by reducing iron levels in human macrophages. Sci Rep. 8;8(1):7296.
  • Abreu, R., P. Giri, and  Quinn. 2020. Interferon-γ promotes iron export in human macrophages to limit intracellular bacterial replication. PLOS ONE. PLoS One. Dec 8;15(12):e0240949.
  • Alyamani EJ, Marcus SA, Ramirez-Busby SM, Hansen C, Rashid J, El-Kholy A, et al. Publisher Correction: Genomic analysis of the emergence of drug-resistant strains of Mycobacterium tuberculosis in the Middle East. Sci Rep. 2019;9(1):20268; doi: 10.1038/s41598-019-55790-8.
  • Bahr NC, Halupnick R, Linder G, Kiggundu R, Nabeta HW, Williams DA, et al. Delta-like 1 protein, vitamin D binding protein and fetuin for detection of Mycobacterium tuberculosis meningitis. Biomark Med. 2018;12(7):707-16; doi: 10.2217/bmm-2017-0373.
  • Baker JJ, Abramovitch RB. Genetic and metabolic regulation of Mycobacterium tuberculosis acid growth arrest. Sci Rep. 2018;8(1):4168; doi: 10.1038/s41598-018-22343-4.
  • Baker JJ, Dechow SJ, Abramovitch RB. Acid Fasting: Modulation of Mycobacterium tuberculosis Metabolism at Acidic pH. Trends Microbiol. 2019;27(11):942-53; doi: 10.1016/j.tim.2019.06.005.
  • Carneiro PAM, Pasquatti TN, Takatani H, Zumarraga MJ, Marfil MJ, Barnard C, et al. Molecular characterization of Mycobacterium bovis infection in cattle and buffalo in Amazon Region, Brazil. Vet Med Sci. 2020;6(1):133-41; doi: 10.1002/vms3.203.
  • Daniel-Wayman S, Abate G, Barber DL, Bermudez LE, Coler RN, Cynamon MH, et al. Advancing Translational Science for Pulmonary Nontuberculous Mycobacterial Infections. A Road Map for Research. Am J Respir Crit Care Med. 2019;199(8):947-51; doi: 10.1164/rccm.201807-1273PP.
  • Gomez-Buendia A, Romero B, Bezos J, Lozano F, de Juan L, Alvarez J. Spoligotype-specific risk of finding lesions in tissues from cattle infected by Mycobacterium bovis. BMC Vet Res. 2021;17(1):148; doi: 10.1186/s12917-021-02848-3.
  • Grooms DL, Bolin SR, Plastow JL, Lim A, Hattey J, Durst PT, et al. Survival of Mycobacterium bovis during forage ensiling. Am J Vet Res. 2019;80(1):87-94; doi: 10.2460/ajvr.80.1.87.
  • Grosse-Siestrup, B.T., T. Gupta, S. Helms, S.L. Tucker, M.I. Voskuil, D. Quinn, and R.K.  Karls. 2021. A role for Mycobacterium tuberculosissigma factor C in copper nutritional immunity. Int J Mol Sci. 22(4):2118.
  • Kuo CJ, Gao J, Huang JW, Ko TP, Zhai C, Ma L, et al. Functional and structural investigations of fibronectin-binding protein Apa from Mycobacterium tuberculosis. Biochim Biophys Acta Gen Subj. 2019;1863(9):1351-9; doi: 10.1016/j.bbagen.2019.06.003.
  • Steinbach S, Jalili-Firoozinezhad S, Srinivasan S, Melo MB, Middleton S, Konold T, et al. Temporal dynamics of intradermal cytokine response to tuberculin in Mycobacterium bovis BCG-vaccinated cattle using sampling microneedles. Sci Rep. 2021;11(1):7074; doi: 10.1038/s41598-021-86398-6.
  • Verteramo Chiu LJ, Tauer LW, Grohn YT, Smith RL. Mastitis risk effect on the economic consequences of paratuberculosis control in dairy cattle: A stochastic modeling study. PLoS One. 2019;14(9):e0217888; doi: 10.1371/journal.pone.0217888.
  • Wanzala SI, Nakavuma J, Travis D, Kia P, Ogwang S, Waters WR, et al. Retrospective Analysis of Archived Pyrazinamide Resistant Mycobacterium tuberculosis Complex Isolates from Uganda-Evidence of Interspecies Transmission. Microorganisms. 2019;7(8); doi: 10.3390/microorganisms7080221
  • Yassine, E., R. Galiwango, W. Ssengooba, F. Ashaba, M.L. Joloba, S. Zalwango, C. Whalen, and  Quinn. 2021. Assessing transmission of Mycobacterium tuberculosisin a defined social network using single nucleotide polymorphism threshold analysis. Microbiologyopen. 2021 Jun;10(3):e1211. doi: 10.1002/mbo3.1211.

 

 

Objective 4: Vaccine development

 

  • Abdelaal HFM, Spalink D, Amer A, Steinberg H, Hashish EA, Nasr EA, et al. Genomic Polymorphism Associated with the Emergence of Virulent Isolates of Mycobacterium bovis in the Nile Delta. Sci Rep. 2019;9(1):11657; doi: 10.1038/s41598-019-48106-3.
  • Abreu R, Giri P, Quinn F. Host-Pathogen Interaction as a Novel Target for Host-Directed Therapies in Tuberculosis. Front Immunol. 2020;11:1553; doi: 10.3389/fimmu.2020.01553.
  • Ali ZI, Hanafy M, Hansen C, Saudi AM, Talaat AM. Genotypic analysis of nontuberculous mycobacteria isolated from raw milk and human cases in Wisconsin. J Dairy Sci. 2021;104(1):211-20; doi: 10.3168/jds.2020-18214.
  • Alyamani EJ, Marcus SA, Ramirez-Busby SM, Hansen C, Rashid J, El-Kholy A, et al. Genomic analysis of the emergence of drug-resistant strains of Mycobacterium tuberculosis in the Middle East. Sci Rep. 2019;9(1):4474; doi: 10.1038/s41598-019-41162-9.
  • Chen Y, Danelishvili L, Rose SJ, Bermudez LE. Mycobacterium bovis BCG Surface Antigens Expressed under the Granuloma-Like Conditions as Potential Inducers of the Protective Immunity. Int J Microbiol. 2019;2019:9167271; doi: 10.1155/2019/9167271.
  • Gupta, T, M. LaGatta, S. Helms, R.L. Pavlicek, S.O. Owino, K. Sakamoto, T. Nagy, S.B. Harvey, M. Papania, S. Ledden, K.T. Schultz, C. McCombs, D.Quinn, and RK Karls. 2018. Evaluation of a temperature-restricted, mucosal tuberculosis vaccine in guinea pigs. Tuberculosis. 113:179-188.
  • Marais, B.J., B.M. Buddle, L-M. de Klerk-Lorist, P. Nguipdop-Djomo,  Quinn, and C. Greenblatt. 2019. BCG vaccination for bovine tuberculosis; conclusions from the Jerusalem One Health Workshop. Transbound Emerging Dis. 66(2):1037-1043.
  • Srinivasan S, Conlan AJK, Easterling LA, Herrera C, Dandapat P, Veerasami M, et al. A Meta-Analysis of the Effect of Bacillus Calmette-Guerin Vaccination Against Bovine Tuberculosis: Is Perfect the Enemy of Good? Front Vet Sci. 2021;8:637580; doi: 10.3389/fvets.2021.637580.

 

Objective 5: Extension and outreach

 

 

 

 

JD publications 2018-2021

 

Objective 1: Epidemiology

 

  • Alvarez, J., D. Bakker, and J. Bezos, Editorial: Epidemiology and Control of Notifiable Animal Diseases. Front Vet Sci, 2019. 6: p. 43.
  • Barkema HW, Orsel K, Nielsen SS, Koets AP, Rutten VPMG, Bannantine JP, Keefe GP, Kelton DF, Wells SJ, Whittington RJ, Mackintosh CG, Manning EJ, Weber MF, Heuer C, Forde TL, Ritter C, Roche S, Corbett CS, Wolf R, Griebel PJ, Kastelic JP, De Buck J. 2018. Knowledge gaps that hamper prevention and control of Mycobacterium avium subspecies paratuberculosis infection. Transbound Emerg Dis. 65 Suppl 1:125-148.
  • Giannitti, F., M. Fraga, R.D. Caffarena, C.O. Schild, G. Banchero, A.G. Armien, G. Traveria, D. Marthaler, S.J. Wells, and F. Riet-Correa, Mycobacterium paratuberculosis sheep type strain in Uruguay: Evidence for a wider geographic distribution in South America. J Infect Dev Ctries, 2018. 12(3): p. 190-195.
  • Kanankege KS, Nicholas B. Phelps, Heidi Vesterinen, Kaylee M. Errecaborde, Julio Alvarez, Jeffrey B. Bender, Scott Wells, Andres M. Perez. 2020. Lessons learned from the stakeholder engagement in research: application of spatial analytical tools in One Health problems. Frontiers, 7:254.
  • Kanankege KST, Machado G, Zhang L, Dokkebakken B, Schumann V, Wells SJ, Perez AM, Alvarez J.  2019. Use of a voluntary testing program to study the spatial epidemiology of Johne’s disease affecting dairy herds in Minnesota: A cross sectional study.  BMC Vet Research, 15:429.
  • Machado, G., K. Kanankege, V. Schumann, S. Wells, A. Perez, and J. Alvarez, Identifying individual animal factors associated with Mycobacterium avium subsp. paratuberculosis (MAP) milk ELISA positivity in dairy cattle in the Midwest region of the United States. BMC Vet Res, 2018. 14(1): p. 28.
  • Samba-Louaka, A., E. Robino, T. Cochard, M. Branger, V. Delafont, W. Aucher, W. Wambeke, J.P. Bannantine, F. Biet, and Y. Hechard, Environmental Mycobacterium avium subsp. paratuberculosis Hosted by Free-Living Amoebae. Front Cell Infect Microbiol, 2018. 8: p. 28.
  • Smiley Evans, T., Z. Shi, M. Boots, W. Liu, K.J. Olival, X. Xiao, S. Vandewoude, H. Brown, J.L. Chen, D.J. Civitello, L. Escobar, Y. Grohn, H. Li, K. Lips, Q. Liu, J. Lu, B. Martinez-Lopez, J. Shi, X. Shi, B. Xu, L. Yuan, G. Zhu, and W.M. Getz, Synergistic China-US Ecological Research is Essential for Global Emerging Infectious Disease Preparedness. Ecohealth, 2020. 17(1): p. 160-173.
  • Stabel, J.R., J.P. Bannantine, and J.M. Hostetter, Comparison of Sheep, Goats, and Calves as Infection Models for Mycobacterium avium subsp. paratuberculosis. Vet Immunol Immunopathol, 2020. 225: p. 110060.
  • Whittington, R., K. Donat, M.F. Weber, D. Kelton, S.S. Nielsen, S. Eisenberg, N. Arrigoni, R. Juste, J.L. Saez, N. Dhand, A. Santi, A. Michel, H. Barkema, P. Kralik, P. Kostoulas, L. Citer, F. Griffin, R. Barwell, M.A.S. Moreira, I. Slana, H. Koehler, S.V. Singh, H.S. Yoo, G. Chavez-Gris, A. Goodridge, M. Ocepek, J. Garrido, K. Stevenson, M. Collins, B. Alonso, K. Cirone, F. Paolicchi, L. Gavey, M.T. Rahman, E. de Marchin, W. Van Praet, C. Bauman, G. Fecteau, S. McKenna, M. Salgado, J. Fernandez-Silva, R. Dziedzinska, G. Echeverria, J. Seppanen, V. Thibault, V. Fridriksdottir, A. Derakhshandeh, M. Haghkhah, L. Ruocco, S. Kawaji, E. Momotani, C. Heuer, S. Norton, S. Cadmus, A. Agdestein, A. Kampen, J. Szteyn, J. Frossling, E. Schwan, G. Caldow, S. Strain, M. Carter, S. Wells, M. Munyeme, R. Wolf, R. Gurung, C. Verdugo, C. Fourichon, T. Yamamoto, S. Thapaliya, E. Di Labio, M. Ekgatat, A. Gil, A.N. Alesandre, J. Piaggio, A. Suanes, and J.H. de Waard, Control of paratuberculosis: who, why and how. A review of 48 countries. BMC Vet Res, 2019. 15(1): p. 198.

 

Objective 2: Diagnostics

 

  • Abdellrazeq, G.S., L.M. Fry, M.M. Elnaggar, J.P. Bannantine, D.A. Schneider, W.M. Chamberlin, A.H.A. Mahmoud, K.T. Park, V. Hulubei, and W.C. Davis, Simultaneous cognate epitope recognition by bovine CD4 and CD8 T cells is essential for primary expansion of antigen-specific cytotoxic T-cells following ex vivo stimulation with a candidate Mycobacterium avium subsp. paratuberculosis peptide vaccine. Vaccine, 2020. 38(8): p. 2016-2025.
  • Bannantine, J.P., J.R. Stabel, D.O. Bayles, C. Conde, and F. Biet, Diagnostic Sequences That Distinguish M. avium Subspecies Strains. Front Vet Sci, 2020. 7: p. 620094.
  • Bay, S., D. Begg, C. Ganneau, M. Branger, T. Cochard, J.P. Bannantine, H. Kohler, J.L. Moyen, R.J. Whittington, and F. Biet, Engineering Synthetic Lipopeptide Antigen for Specific Detection of Mycobacterium avium subsp. paratuberculosis Infection. Front Vet Sci, 2021. 8: p. 637841.
  • Cinar, M.U., B. Akyuz, K. Arslan, S.N. White, H.L. Neibergs, and K.S. Gumussoy, The EDN2 rs110287192 gene polymorphism is associated with paratuberculosis susceptibility in multibreed cattle population. PLoS One, 2020. 15(9): p. e0238631.
  • Conde, C., M. Price-Carter, T. Cochard, M. Branger, K. Stevenson, R. Whittington, J.P. Bannantine, and F. Biet, Whole-Genome Analysis of Mycobacterium avium subsp. paratuberculosis IS900 Insertions Reveals Strain Type-Specific Modalities. Front Microbiol, 2021. 12: p. 660002.
  • Greenstein, R.J., L. Su, P.S. Fam, J.R. Stabel, and S.T. Brown, Failure to detect M. avium subspecies paratuberculosis in Johne's disease using a proprietary fluorescent in situ hybridization assay. BMC Res Notes, 2018. 11(1): p. 498.
  • Jenvey, C.J., J.M. Hostetter, A.L. Shircliff, and J.R. Stabel, Relationship between the pathology of bovine intestinal tissue and current diagnostic tests for Johne's disease. Vet Immunol Immunopathol, 2018. 202: p. 93-101.
  • Li, L., J.P. Bannantine, J.J. Campo, A. Randall, Y.T. Grohn, M.A. Schilling, R. Katani, J. Radzio-Basu, L. Easterling, and V. Kapur, Identification of Sero-Diagnostic Antigens for the Early Diagnosis of Johne's Disease using MAP Protein Microarrays. Sci Rep, 2019. 9(1): p. 17573.
  • Machado G, Kanankege KST, Schumann V, Wells SJ, Perez AM, Alvarez J. Identifying individual animal factors associated with Mycobacterium avium subsp. paratuberculosis (MAP) milk ELISA positivity in dairy cattle in the Midwest region of the United States. BMC Vet Res 14(1):28.
  • Picasso-Risso, C., A. Grau, D. Bakker, J. Nacar, O. Minguez, A. Perez, and J. Alvarez, Association between results of diagnostic tests for bovine tuberculosis and Johne's disease in cattle. Vet Rec, 2019. 185(22): p. 693.
  • Richards, V.P., A. Nigsch, P. Pavinski Bitar, Q. Sun, T. Stuber, K. Ceres, R.L. Smith, S. Robbe Austerman, Y. Schukken, Y.T. Grohn, and M.J. Stanhope, Evolutionary genomic and bacteria GWAS analysis of Mycobacterium avium subsp. paratuberculosis and dairy cattle Johne's disease phenotypes. Appl Environ Microbiol, 2021.

 

 

Objective 3: Biology and Pathogenesis

 

  • Al-Mamun, M.A., R.L. Smith, A. Nigsch, Y.H. Schukken, and Y.T. Grohn, A data-driven individual-based model of infectious disease in livestock operation: A validation study for paratuberculosis. PLoS One, 2018. 13(12): p. e0203177.
  • Babrak, L. and L.E. Bermudez, Response of the respiratory mucosal cells to mycobacterium avium subsp. Hominissuis microaggregate. Arch Microbiol, 2018. 200(5): p. 729-742.
  • Bannantine, J.P. and D.O. Bayles, Draft Genome Sequences of Two Bison-Type and Two Sheep-Type Strains of Mycobacterium avium subsp. paratuberculosis. Microbiol Resour Announc, 2021. 10(28): p. e0052621.
  • Bannantine, J.P., A. Wadhwa, J.R. Stabel, and S. Eda, Characterization of Ethanol Extracted Cell Wall Components of Mycobacterium avium Subsp. paratuberculosis. Vet Sci, 2019. 6(4).
  • Bannantine, J.P., C. Conde, D.O. Bayles, M. Branger, and F. Biet, Genetic Diversity Among Mycobacterium avium Subspecies Revealed by Analysis of Complete Genome Sequences. Front Microbiol, 2020. 11: p. 1701.
  • Bannantine, J.P., D.K. Zinniel, and R.G. Barletta, Transposon Mutagenesis in Mycobacterium avium Subspecies Paratuberculosis. Methods Mol Biol, 2019. 2016: p. 117-125.
  • Bannantine, J.P., D.O. Bayles, and F. Biet, Complete Genome Sequence of a Type III Ovine Strain of Mycobacterium avium subsp. paratuberculosis. Microbiol Resour Announc, 2021. 10(10).
  • Bannantine, J.P., J.R. Stabel, J.D. Lippolis, and T.A. Reinhardt, Membrane and Cytoplasmic Proteins of Mycobacterium avium subspecies paratuberculosis that Bind to Novel Monoclonal Antibodies. Microorganisms, 2018. 6(4).
  • Bechler, J. and L.E. Bermudez, Investigating the Role of Mucin as Frontline Defense of Mucosal Surfaces against Mycobacterium avium Subsp. hominissuis. J Pathog, 2020. 2020: p. 9451591.
  • Bermudez, L.E., S.J. Rose, J.L. Everman, and N.R. Ziaie, Establishment of a Host-to-Host Transmission Model for Mycobacterium avium subsp. hominissuis Using Caenorhabditis elegans and Identification of Colonization-Associated Genes. Front Cell Infect Microbiol, 2018. 8: p. 123.
  • Blanchard, J.D., V. Elias, D. Cipolla, I. Gonda, and L.E. Bermudez, Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin. Antimicrob Agents Chemother, 2018. 62(10).
  • Caldeira, J.L.A., A.C.S. Faria, E.A. Diaz-Miranda, T.J. Zilch, S.L. da Costa Caliman, D.S. Okano, J.D. Guimaraes, J.L. Pena, W.F. Barbosa, A.S. Junior, Y.F. Chang, and M.A.S. Moreira, Interaction of Mycobacterium avium subsp. paratuberculosis with bovine sperm. Theriogenology, 2021. 161: p. 228-236.
  • Chiplunkar, S.S., C.A. Silva, L.E. Bermudez, and L. Danelishvili, Characterization of membrane vesicles released by Mycobacterium avium in response to environment mimicking the macrophage phagosome. Future Microbiol, 2019. 14: p. 293-313.
  • Danelishvili, L., E. Armstrong, E. Miyasako, B. Jeffrey, and L.E. Bermudez, Exposure of Mycobacterium avium subsp. homonissuis to Metal Concentrations of the Phagosome Environment Enhances the Selection of Persistent Subpopulation to Antibiotic Treatment. Antibiotics (Basel), 2020. 9(12).
  • Danelishvili, L., R. Rojony, K.L. Carson, A.L. Palmer, S.J. Rose, and L.E. Bermudez, Mycobacterium avium subsp. hominissuis effector MAVA5_06970 promotes rapid apoptosis in secondary-infected macrophages during cell-to-cell spread. Virulence, 2018. 9(1): p. 1287-1300.
  • DeKuiper, J.L. and P.M. Coussens, Inflammatory Th17 responses to infection with Mycobacterium avium subspecies paratuberculosis (MAP) in cattle and their potential role in development of Johne's disease. Vet Immunol Immunopathol, 2019. 218: p. 109954.
  • DeKuiper, J.L. and P.M. Coussens, Mycobacterium avium sp. paratuberculosis (MAP) induces IL-17a production in bovine peripheral blood mononuclear cells (PBMCs) and enhances IL-23R expression in-vivo and in-vitro. Vet Immunol Immunopathol, 2019. 218: p. 109952.
  • DeKuiper, J.L., H.E. Cooperider, N. Lubben, C.M. Ancel, and P.M. Coussens, Mycobacterium avium Subspecies paratuberculosis Drives an Innate Th17-Like T Cell Response Regardless of the Presence of Antigen-Presenting Cells. Front Vet Sci, 2020. 7: p. 108.
  • Everman, J.L., L. Danelishvili, L.G. Flores, and L.E. Bermudez, MAP1203 Promotes Mycobacterium avium Subspecies paratuberculosis Binding and Invasion to Bovine Epithelial Cells. Front Cell Infect Microbiol, 2018. 8: p. 217.
  • Franceschi, V., A.H. Mahmoud, G.S. Abdellrazeq, G. Tebaldi, F. Macchi, L. Russo, L.M. Fry, M.M. Elnaggar, J.P. Bannantine, K.T. Park, V. Hulubei, S. Cavirani, W.C. Davis, and G. Donofrio, Capacity to Elicit Cytotoxic CD8 T Cell Activity Against Mycobacterium avium subsp. paratuberculosis Is Retained in a Vaccine Candidate 35 kDa Peptide Modified for Expression in Mammalian Cells. Front Immunol, 2019. 10: p. 2859.
  • Hosseiniporgham, S., F. Biet, C. Ganneau, J.P. Bannantine, S. Bay, and L.A. Sechi, A Comparative Study on the Efficiency of Two Mycobacterium avium subsp. paratuberculosis (MAP)-Derived Lipopeptides of L3P and L5P as Capture Antigens in an In-House Milk ELISA Test. Vaccines (Basel), 2021. 9(9).
  • Jenvey, C.J., J.M. Hostetter, A.L. Shircliff, J.P. Bannantine, and J.R. Stabel, Quantification of Macrophages and Mycobacterium avium Subsp. paratuberculosis in Bovine Intestinal Tissue During Different Stages of Johne's Disease. Vet Pathol, 2019. 56(5): p. 671-680.
  • Johnson, B.K., S.M. Thomas, A.J. Olive, and R.B. Abramovitch, Macrophage Infection Models for Mycobacterium tuberculosis. Methods Mol Biol, 2021. 2314: p. 167-182.
  • Kiser, J.N., Z. Wang, R. Zanella, E. Scraggs, M. Neupane, B. Cantrell, C.P. Van Tassell, S.N. White, J.F. Taylor, and H.L. Neibergs, Functional Variants Surrounding Endothelin 2 Are Associated With Mycobacterium avium Subspecies paratuberculosis Infection. Front Vet Sci, 2021. 8: p. 625323.
  • Lewis, M.S., L. Danelishvili, S.J. Rose, and L.E. Bermudez, MAV_4644 Interaction with the Host Cathepsin Z Protects Mycobacterium avium subsp. hominissuis from Rapid Macrophage Killing. Microorganisms, 2019. 7(5).
  • Nigsch, A., S. Robbe-Austerman, T.P. Stuber, P.D. Pavinski Bitar, Y.T. Grohn, and Y.H. Schukken, Who infects whom?-Reconstructing infection chains of Mycobacterium avium ssp. paratuberculosis in an endemically infected dairy herd by use of genomic data. PLoS One, 2021. 16(5): p. e0246983.
  • Nigsh, A., Robbe-Austerman, S., Stuber, T.P., Pavinski Bitar, P.D., Gr√∂hn Y.T., Schukken, Y.H.: Who infects Whom? - Reconstructing infection chains of Mycobacterium avium ssp. paratuberculosis in an endemically infected dairy herd by use of genomic data. PLOS ONE, 2021 https://doi.org/10.1371/journal.pone.0246983
  • Palcekova, Z., M. Gilleron, S.K. Angala, J.M. Belardinelli, M. McNeil, L.E. Bermudez, and M. Jackson, Polysaccharide Succinylation Enhances the Intracellular Survival of Mycobacterium abscessus. ACS Infect Dis, 2020. 6(8): p. 2235-2248.
  • Phillips, I.L., J.L. Everman, L.E. Bermudez, and L. Danelishvili, Acanthamoeba castellanii as a Screening Tool for Mycobacterium avium Subspecies paratuberculosis Virulence Factors with Relevance in Macrophage Infection. Microorganisms, 2020. 8(10).
  • Phillips, I.L., L. Danelishvili, and L.E. Bermudez, Macrophage Proteome Analysis at Different Stages of Mycobacterium avium Subspecies paratuberculosis Infection Reveals a Mechanism of Pathogen Dissemination. Proteomes, 2021. 9(2).
  • Rojony, R., L. Danelishvili, A. Campeau, J.M. Wozniak, D.J. Gonzalez, and L.E. Bermudez, Exposure of Mycobacterium abscessus to Environmental Stress and Clinically Used Antibiotics Reveals Common Proteome Response among Pathogenic Mycobacteria. Microorganisms, 2020. 8(5).
  • Rojony, R., M. Martin, A. Campeau, J.M. Wozniak, D.J. Gonzalez, P. Jaiswal, L. Danelishvili, and L.E. Bermudez, Quantitative analysis of Mycobacterium avium subsp. hominissuis proteome in response to antibiotics and during exposure to different environmental conditions. Clin Proteomics, 2019. 16: p. 39.
  • Shoyama, F.M., T. Janetanakit, J.P. Bannantine, R.G. Barletta, and S. Sreevatsan, Elucidating the Regulon of a Fur-like Protein in Mycobacterium avium subsp. paratuberculosis (MAP). Front Microbiol, 2020. 11: p. 598.
  • Silva, C., R. Rojony, L.E. Bermudez, and L. Danelishvili, Short-Chain Fatty Acids Promote Mycobacterium avium subsp. hominissuis Growth in Nutrient-Limited Environments and Influence Susceptibility to Antibiotics. Pathogens, 2020. 9(9).
  • Stabel, J., L. Krueger, C. Jenvey, T. Wherry, J. Hostetter, and D. Beitz, Influence of Colostrum and Vitamins A, D3, and E on Early Intestinal Colonization of Neonatal Holstein Calves Infected with Mycobacterium avium subsp. paratuberculosis. Vet Sci, 2019. 6(4).
  • Zinniel, D.K., W. Sittiwong, D.D. Marshall, G. Rathnaiah, I.T. Sakallioglu, R. Powers, P.H. Dussault, and R.G. Barletta, Novel Amphiphilic Cyclobutene and Cyclobutane cis-C18 Fatty Acid Derivatives Inhibit Mycobacterium avium subsp. paratuberculosis Growth. Vet Sci, 2019. 6(2).

 

Objective 4: Vaccine development

 

  • Berry, A., C.W. Wu, A.J. Venturino, and A.M. Talaat, Biomarkers for Early Stages of Johne's Disease Infection and Immunization in Goats. Front Microbiol, 2018. 9: p. 2284.
  • Phanse, Y., C.W. Wu, A.J. Venturino, C. Hansen, K. Nelson, S.R. Broderick, H. Steinberg, and A.M. Talaat, A Protective Vaccine against Johne's Disease in Cattle. Microorganisms, 2020. 8(9).
  • Thukral, A., K. Ross, C. Hansen, Y. Phanse, B. Narasimhan, H. Steinberg, and A.M. Talaat, A single dose polyanhydride-based nanovaccine against paratuberculosis infection. NPJ Vaccines, 2020. 5(1): p. 15.

 

Objective 5: Extension and outreach

 

 

  • Cochard, T., M. Branger, P. Supply, S. Sreevatsan, and F. Biet, MAC-INMV-SSR: a web application dedicated to genotyping members of Mycobacterium avium complex (MAC) including Mycobacterium avium subsp. paratuberculosis strains. Infect Genet Evol, 2020. 77: p. 104075.
  • Kanankege, K.S.T., N.B.D. Phelps, H.M. Vesterinen, K.M. Errecaborde, J. Alvarez, J.B. Bender, S.J. Wells, and A.M. Perez, Lessons Learned From the Stakeholder Engagement in Research: Application of Spatial Analytical Tools in One Health Problems. Front Vet Sci, 2020. 7: p. 254.
  • Kelly, T.R., D.A. Bunn, N.P. Joshi, D. Grooms, D. Devkota, N.R. Devkota, L.N. Paudel, A. Roug, D.J. Wolking, and J.A.K. Mazet, Awareness and Practices Relating to Zoonotic Diseases Among Smallholder Farmers in Nepal. Ecohealth, 2018. 15(3): p. 656-669.
  • Verteramo Chiu, L.J., L.W. Tauer, M.A. Al-Mamun, K. Kaniyamattam, R.L. Smith, and Y.T. Grohn, An agent-based model evaluation of economic control strategies for paratuberculosis in a dairy herd. J Dairy Sci, 2018. 101(7): p. 6443-6454.

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