Bovine respiratory disease (BRD) is the leading cause of mortality for all classes of cattle and calves in the United States (USDA, 2006). In 2006, respiratory disease accounted for 28.7% of all deaths, with losses due to animal death alone costing producers over $692 million annually (USDA, 2006). This estimate does not include cost of medication, labor, and production losses associated with respiratory disease; those costs, which have not been well estimated, likely increase all BRD-related losses to over $1 billion per year (Ishmael, 2001; Kapil and Basaraba, 1997). Thus BRD has a significant impact on profitability of U.S. cattle operations, as well as a significant impact on well-being of U.S. cattle. Recent NAHMS surveys also confirm that BRD is the leading cause of morbidity and mortality in U.S. feedlots (USDA, 2011), the most common cause of nursing dairy calf mortality, and the leading cause of weaned dairy heifer mortality (USDA, 2014). BRD is the result of multiple factors acting in concert. Infection by viral and bacterial respiratory pathogens causes the pathologic lesions characteristic of BRD (Woolums et al., 2009). Viral infection is nearly always the primary infectious insult, with subsequent infection by opportunistic bacterial organisms exacerbating the resulting lung pathology. The viral agents most commonly involved in BRDC include bovine herpesvirus-1 (BHV-1), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), parainfluenza type 3 virus (PI-3V), and bovine respiratory coronavirus (BRCV); the predominant bacterial agents include Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis (Fulton et al., 2009a; Gagea et al., 2006). Other agents may be found in isolated cases. When BRD affects a group of cattle, various combinations of multiple viral and bacterial agents are typically involved. However, the viral pathogens of BRD can also be found to circulate in cattle showing few or no signs of disease, and the bacterial pathogens can be identified as part of the normal flora of the nasopharynx in healthy cattle. Since the microbial pathogens of BRD may cause little or no disease, factors other than respiratory infection must be necessary to induce BRD. The additional necessary factors are related to 1) the bovine host’s specific ability to resist disease following respiratory infection and 2) the way cattle are managed, including factors such as mixing animals from multiple sources, transportation, and weaning, castration, and/or dehorning immediately prior to shipment and mixing (Fulton, 2009a; Taylor et al., in press). Thus, BRD needs to be considered a disease complex and must be approached by attacking the multiple etiologies involved in its occurrence. Although BRD is an important cause of cattle morbidity and mortality, research carried out by members of NC-1192 has improved our understanding of some aspects of the problem. Genetic factors associated with BRD susceptibility have been explored with promising results (Zanella et al., 2011; Neibergs et al., 2015). Significant efforts have also been directed at improving clinical BRD diagnosis. NC-1192 members have developed enhance scoring systems to improve BRD diagnosis in dairy calves (Aly et al., 2014; Love et al., 2014). Efforts by many NC-1192 members to characterize virulence factors are ongoing. See more examples in the section “Related, Current and Previous Work”. Although these discoveries have improved foundational knowledge regarding the causes of BRD, and have revealed pathways amenable to mitigating the disease in at least some groups of cattle, gaps in our knowledge of factors that contribute to BRD persist. New pathogens have recently been identified to predominate in BRD in some cattle (Fulton et al, 2009b; Gagea et al, 2006), but it is not known whether these agents have gained a foothold because of particular pathogenic mechanisms or because of changes in management that predispose cattle to infection by them. Rapid identification of pathogens, ideally at “chute-side”, could help manage cattle with BRD in ways to better limit spread of disease, but rapid tests for BRD pathogens are as yet not available. Management of co-infections, such as gastrointestinal parasitism, may impact the ability of cattle to respond to respiratory infection, but little research has yet evaluated the impact of parasitism or other non-respiratory infections on BRD. While vaccines that improve the immune response to BRD are widely used and can be efficacious, factors which limit their impact need to be addressed; among these include the fact that vaccination is sometimes but not always effective in calves with circulating maternal antibody, and for some infectious agents, vaccines are not available, or have not been confirmed to be effective in the field. These and other knowledge gaps will be addressed by research in the proposed NC-1192 project. The importance of the work described is that the combined effort of members of NC-1192 is the most broad, collaborative, and multidisciplinary effort to ameliorate BRD in North America. If the described research is not undertaken, it will not be possible for veterinarians and producers to develop science-based approaches to minimize or prevent BRD in cattle managed under modern U.S. husbandry practices. While the work described is technically and logistically challenging, scientists at the participating stations have the necessary experience and skills to carry out the proposed research. The group will consist of a team of researchers with a broad range of experience with the techniques necessary to undertake the research. Participating researchers possess the necessary contemporary skills in molecular biology, immunology, virology, bacteriology, and animal management to carry out research to test relevant hypotheses and to then develop science-based integrated diagnostic and preventative strategies. Ongoing progress of useful research by NC-1192 can be improved by interaction with researchers outside NC-1192, including those in government laboratories and in the pharmacologics/biologics industry, and with veterinary practitioners, cattle producers, and other stakeholders. Members of NC-1192 have worked hard to develop relationships with national organizations to allow for substantial dialog to occur regarding the unanswered questions and persistent problems related to BRD. This “two way street” has helped researchers understand ongoing and new challenges that the industry faces while at the same time allowing us to articulate challenges that researchers face in conducting relevant research that meets the industry’s needs. This open dialog has in part been responsible for increased funding being made available to fund much needed BRD research. Ultimately, the value of the research proposed here is most significant only if it is translated from research discovery to field application. NC-1192 prides itself in being a primary source of information about BRD for veterinarians and producers. Its research effort helps to provide better surveillance of the causes of BRD, improves understanding of the complex molecular events involved in BRD polymicrobial infections, visualizes and tests new management strategies, and articulates a cutting-edge team approach that coordinates new knowledge with validated practices. Through integrated efforts, we will facilitate the dissemination of this information, as well as that developed by other BRD initiatives, to the beef and dairy industry where is can be applied. Impacts of the proposed research will include: 1. Veterinarians and cattle producers will have access to science-based recommendations for the control and prevention of BRD in cattle managed in modern U.S. production systems; 2. Researchers in academic, government, and industry laboratories will be provided with basic foundational and applied information regarding BRD that will be necessary for their their ongoing work to advance scientific discovery in the fields of vaccinology, immunology, microbiology, pharmacology, and animal husbandry; 3. Scientists, veterinarians, and policy makers working to minimize unnecessary use of antimicrobials will be provided with basic and applied information regarding methods to enhance resistance to BRD by maximizing the use of vaccines and management strategies that will minimize the need for antimicrobials; 4. Scientists, educators, and policy makers will be provided with cutting-edge information regarding the mechanisms by which cattle develop BRD, and regarding science-based methods to minimize or prevent the impacts of BRD; 5. Veterinarians and cattle producers will be regularly educated regarding both new developments in the science of BRD, and in rational and practical methods to limit the impact of BRD in U.S. cattle.