Duration: 10/01/2021 to 09/30/2026

Administrative Advisor(s):

NIFA Reps:

Non-Technical Summary

Statement of Issues and Justification

     Bovine respiratory disease is a major cause of morbidity and mortality in cattle in the United States. This complex disease is caused by the combination of multiple factors, including various viral and bacterial pathogens and environmental and management-related stressors. The illness affects all segments of the cattle industry and all classes of cattle. A previous report indicated that BRD affects 16.2% of all cattle at feedlots, and 96.9% of feedlots reported cases of BRD (USDA, 2013). Even though there is a lack of information about the incidence of BRD in the stocker sector, it is possible that BRD occurrence at this segment is higher than that reported for feedlots, due to stress associated with management practices and the young/lightweight state of cattle in these operations. In cow-calf operations, BRD is responsible for 31.4% of total pre-weaning calf mortality (USDA, 2010). In the dairy industry, BRD was reported by 60.5% of dairy operations (USDA, 2018) and accounts for 24.0% and 58.9% of mortality in pre-weaned and weaned dairy heifers, respectively (USDA, 2018). According to the USDA, BRD accounted for 23.9% of deaths in cattle. This mortality results in economic losses of $907.8 million (USDA, 2017). This calculation does not include costs of treatment, labor, and production losses associated with BRD; those costs, which have not been well estimated, likely increase all BRD-related losses to over $1 billion per year (Ishmael, 2001).

 

     Bovine respiratory disease is a multifactorial and polymicrobial illness caused by viral and bacterial co-infections. Viral agents such as Bovine viral diarrhea virus (BVDV), Bovine respiratory syncytial virus (BRSV) Bovine herpes virus 1 (BHV1), Bovine parainfluenza 3 virus (BPI3V) are commonly involved as causative agents. Commensal bacteria of the upper respiratory tract including Mannheimia haemolytica and Pasteurella multocida, can often cause secondary infections that complicate the pathogenesis of BRD and may result in severe illness. In addition, Histophilus somni and Mycoplasma bovis often contribute as causal microorganisms of BRD. These pathogens elaborate virulence factors that allow them to evade clearance by the immune system but can induce significant inflammation (Shirbroun, 2020). In addition, Bovine coronavirus (BCoV) and Influenza D virus (IDV) have been identified in the bovine respiratory tract and have recently gained considerable attention in the etiology of BRD.

 

     Multiple factors influence the occurrence of BRD, including management-environmental conditions, host immune status, and virulence of pathogens. Therefore, BRD control should focus on mitigation of all involved factors. Management practices such as weaning without pre-conditioning, long distance transportation, multi-source comingling and on-arrival castration are major risk factors for BRD. However, the economic pressure of cattle industry and the lack of inducements at the cow-calf operation level limit incentive for significant management improvements that reduce the risk of BRD and the associated economic losses at the subsequent cattle production segments (e.g. feedlot operations). A holistic approach to BRD control should focus on producing less susceptible calves (with stronger immunity) to enter the stocker/back-grounding and feedlots operations, which would result in reduced BRD morbidity and less treatment costs (Peel, 2020). These risk factors that make a calf more susceptible to suffer clinical respiratory disease may affect the host immune interactions at different degrees depending on their genomic background. Research performed by members of the NC1192 identified several differentially expressed genes in whole blood at arrival that revealed clear differences between calves that succumbed with BRD and those that resisted BRD, suggesting the existence of host immune factors that confer protection against BRD (Scott et al., 2020). Further studies have demonstrated that there is a considerable variation in the calves’ response to bacterial lung infection that may represent “tolerance” to pulmonary infection (Bassel et al., 2020). The aforementioned risk factors may affect the host immune interactions resulting in loss of such tolerance that leads to a severe lung inflammatory response after infection. In addition, significant efforts have been directed toward the study of genetic variation of pathogens involved in BRD and virulence factors associated with evasion of the immune response and antimicrobial resistance. A better understanding of this host-environment-pathogen triad and its complex interactions determines the success of BRD control and is one of the main areas of focus of the current NC1192 research project.

 

     Bovine respiratory disease is routinely diagnosed based on clinical signs. Improvement of case definition is crucial to develop reliable tests. Significant efforts of NC1192 have been directed at improving clinical BRD diagnosis. The California Experiment Station developed a clinical scoring system for BRD that allows quick and easy assessment of calves housed in group pens for BRD (Maier et al., 2019). In addition to clinical diagnosis, improvements in diagnosis of infectious agents have been performed and these may help to develop improved control measures. Unfortunately, the clinical significance of some detected pathogens in addition to difficulties in the interpretation of diagnostic tests make BRD diagnosis complex, and reveal huge gaps in the current knowledge. Development of field tests for rapid pathogen detection (e.g. colorimetric spot tests for BRD pathogens) would permit immediate isolation of positive animals limiting disease transmission. Such tests may also have a significant impact on disease control. Practical diagnostic tests for BRD should be meticulously validated based on accuracy, repeatability and agreement before they are used by veterinary practitioners and producers. Diagnostic laboratories have evolved to the use of genomics, developing and validating PCR protocols for virus detection. This has allowed to identify new pathogens from BRD cases (e.g. BCoV and IDV, (Fulton, 2020). However, current investigation should be focused on determining the contribution of such newly identified pathogens in the pathogenesis of BRD.

 

     A review of the scientific literature published during the last 37 years revealed solid evidence of the benefits of vaccinating beef calves around the time of weaning with multivalent modified-live viral (MLV) vaccines reducing BRD morbidity and mortality after weaning. However, it is uncertain if vaccination of young beef calves reduces BRD illness and death before weaning. Regarding vaccination of young dairy calves, there is still conflicting evidence of the efficacy of MLV vaccines on the reduction of BRD morbidity and mortality (Chamorro and Palomares, 2020). It is clear that the level of maternally derived antibodies, the infectious pressure of each farm, and the degree of homology of field versus vaccine virus strains affect the efficacy of BRD vaccination of cattle. Knowledge gaps about diagnosis and efficacy/safety of vaccination will be addressed by research in the proposed NC-1192 project.

 

     The work described in this project is the result of multidisciplinary and collaborative efforts of NC1192 state members and their interaction with other researchers, state diagnostic laboratories, veterinary practitioners, pharmaceutical industry and cattle producers with the long-term goal of preventing and controlling BRD in North America. Multiple research studies will be performed in the areas of epidemiology, molecular biology and genetics, immunopathogenesis of BRD pathogens, bacteriology, virology, diagnostics and vaccinology, nutrition, animal behavior and husbandry to provide science-based recommendations that enhance diagnosis, prevention and treatment for BRD. In addition, members of NC-1192 consistently work to maintain excellent relationships with national organizations such as the American Association of Bovine Practitioners (AABP) and Academy of Veterinary Consultants (AVC) to understand the challenges cattle industry faces and keep a clear focus on the priorities to be investigated regarding BRD. A significant portion of the research performed by NC1192 stations translates into practical applications to cattle production systems. The project’s research efforts help to provide improved information regarding the causes and risk factors associated with the occurrence of BRD, enhances understanding the interactions between pathogens and the host immune response during co-infections, and assesses the accuracy of new diagnostic tools and the efficacy of novel control strategies. Furthermore, recognizing the substantial economic losses caused by BRD, the current NC1192 project is including an additional objective to quantify the economic impact of the disease among the different sectors of cattle industry and how the implementation of control may reduce the incurred losses.

 

     Through integrated efforts, NC1192 will facilitate the dissemination of this information to the cattle industry where it can be applied. An effective way that the NC1192 multistate project has found to share this information with veterinary practitioners and producers is through regional and national events such as the “BRD Symposium” organized by its members every 5 years (www.brdsymposium.org). 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 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, and 6. Cattle producers, veterinarians, and scientists will have updated information regarding the economic impact of BRD, enabling the development of cost-effective control strategies.

Related, Current and Previous Work

 

Members of NC-1192 have identified several knowledge gaps related to the project objectives and have worked consistently in a collaborative manner during the last five years, addressing these knowledge gaps and generating the following research outcomes: 1. Pathogen profiles and loci associated with enhanced resistance to BRD were assessed in 1000 pre-weaned calves through a collaborative multistate (WA, TX, MO, CA) USDA-NIFA funded grant. Bacteriology and virology were used to identify pathogen profiles from mid-nasal and deep pharyngeal swabs and Illumina BovineHD BeadChips were used for genotyping. Genome-wide association results were compared with previous results in pre-weaned dairy calves in California and New Mexico. 2. Genomic analysis of bovine respiratory disease and lung consolidation in pre-weaned Holstein calves diagnosed with BRD using clinical scoring and lung ultrasound was performed through collaborative effort between WI and Zoetis Animal Health. This study revealed that heritability estimates for BRD derived from clinical respiratory scoring and lung ultrasound examination were low to moderate. In addition, reliabilities of genomic predictions were low, due to the small reference population. Significant genetic variation between individuals and families was observed, indicating that genetic selection for animals that are more resistant to BRD infection and more resilient to development of subclinical or clinical lung lesions is likely to be effective. 3. The diversity of Mannheimia haemolytica genotypes and phenotypes on bacterial culture plates using nasopharyngeal swabs (NPS) collected from stocker cattle at arrival or at the time of treatment for BRD was done by researchers from MS in collaboration with NE. A recurring question for BRD researchers is: when bovine NPS are cultured to identify M. haemolytica for characterization of antimicrobial resistance or other factors, how many colonies need to be selected from the plate in order to have a high confidence that all relevant genotypes and phenotypes have been selected? This research addresses this question. In ongoing research, up to 100 colonies have been selected from cultures of NPS collected from 20 stocker cattle. At least one colony of M haemolytica was isolated from seven cattle; antimicrobial susceptibility (phenotype) was assessed by Sensititre and predicted genotype was assessed by MALDI-TOF. NPS from three cattle yielded only one phenotype; three NPS had two phenotypes; and one NPS had three phenotypes. Isolates from a single NPS were genotypically homogenous. When different antibiograms were found this was due to variation in the MIC by one 2- fold dilution. The number of different phenotypes was not large, suggesting that all types might often be identified with selection of relatively few colonies. Work is ongoing to characterize isolates from other cattle and to use Bayesian modeling to estimate the number of colonies that must be selected to identify all phenotypes/genotypes with a high level of confidence. 4. The prevalence and temporal trends in antimicrobial resistance of bovine respiratory disease pathogen isolates was done by WI and SD. P. multocida, and M haemolytica continue to be the most prevalent bacteria isolated from respiratory samples submitted to the WVDL. There is an increase in percent of M. haemolytica and H. somni resistant isolates to commonly used drug classes. Bibersteinia trehalosi was isolated least frequently but showed greatest resistance across all antibiotic classes. 5. A cohort study done by researchers at WI and OH determined the association between automated feeding behaviors and subclinical respiratory disease in preweaned dairy calves. Automated feeding data including drinking speed, consumption, rewarded and unrewarded visits were not able to correctly identify calves with subclinical pneumonia. 6. In another study performed by the same team, behavioral attitude scores associated with bovine respiratory disease were identified using calf lung ultrasound and clinical respiratory scoring. Attitude changes were detected only in calves with clinical BRD as diagnosed by UW Calf Health Score, however the sensitivity was still low. Attitude changes were not detected in calves with subclinical BRD diagnosed by lung ultrasound. 7. Methods to passively survey feedlot cattle for antimicrobial resistant M. haemolytica are being developed through a USDA CEAH funded proposal led by TX in collaboration with MSU. While AMR M. haemolytica are increasingly reported, identification has traditionally required collection of nasopharyngeal swabs from individual cattle. This collaborative research effort between TX and MSU will determine whether sampling of ropes that cattle chew on, or water bowls in feedlots, can provide information regarding the prevalence of AMR M. haemolytica that is comparable to nasopharyngeal swabbing of individual cattle, but with less handling of the cattle. Development of passive methods of sampling cattle for AMR respiratory bacteria will allow better tracking of AMR and its impact in feedlot cattle. Measurement of AMR in feedlot cattle will support the development of improved management practices that decrease the dissemination of AMR. 8. Prompt clinical diagnosis of BRD may reduce its impact by establishing early isolation and treatment of sick animals. Clinical examination and health score for BRD diagnosis may fail to identify cases of subclinical pneumonia. Researchers from GA with the collaboration of AL developed a respiratory endoscopic score (ES) for evaluation of the upper respiratory tract (URT) using a vaccination-challenge model of 60 dairy calves that received MLV vaccination and trace mineral supplementation and were infected with BVDV2 and BHV1. Endoscopic evaluation of the studied calves’ URT showed differences in the appearance of the respiratory mucosa before and after BVDV2 + BHV1 challenge; contrast between vaccinated and unvaccinated calves, as well as the benefits of trace minerals supplementation concurrent with IN vaccination. This study demonstrated that endoscopy may be a valuable tool that permits prompt evaluation of the URT of affected animals, before bronchial and lung lesions develop. 9. While vaccination is generally expected to decrease BRD risk and travel through an auction market is expected to increase BRD risk, there is surprisingly little controlled research that allows for measurement of the degree of effect of these management practices. In collaboration with KS and TX, MS is currently determining the impact of management decisions during the cow-calf, backgrounding, and feedlot phases of beef production on BRD morbidity and mortality risks. This study is evaluating how vaccination against viral respiratory pathogens at 60 days of age, and how transport through a livestock auction, impact morbidity, mortality, and inflammatory response in beef cattle. Inflammatory response before and after day 60 vaccination and before and after transport to the backgrounding facility are being assessed by measurement of serum concentrations of proinflammatory cytokines TNF-alpha and IL-1beta and the acute phase reactant haptoglobin. Rates of morbidity and mortality are being determined in the cow-calf phase, backgrounding phase, and feedlot phase. 10. In collaboration with UGA, MS assessed the plasma concentrations of tulathromycin in cattle following administration by CO2-powered dart gun, pump dart gun, or needle injection, in a 3-way crossover study. 11. Two different BVDV recombinant vaccine studies were performed by SD and KS to compared cross neutralization for 6 different BVDV strains. 12. To evaluate the effect of an intranasal respiratory vaccine protocol on calf health, ultrasonographic lung consolidation, and growth in Holstein dairy calves, a collaborative research project was done between WI, University of Guelph in Ontario, Canada, and NY. Administration of Inforce-3 intranasal vaccine reduced the risk of ultrasonographic lung consolidation and improved growth (minimally) of preweaned dairy calves despite no apparent effect on clinical picture. 13. In order to assess the effect of on-arrival mass treatment of high risk stocker cattle with long acting macrolide on AMR in M. haemolytica a USDA NIFA funded study is in progress by MS and TX. This study is assessing the prevalence of AMR M. haemolytica nasopharyngeal shedding by high risk stocker cattle that are treated with a long acting macrolide antimicrobial at arrival (“metaphylaxis”), vs cattle not receiving metaphylaxis. The researchers are assessing AMR by measuring minimum inhibitory concentrations (MIC) for antimicrobials by M. haemolytica isolated by culture. The study is also assessing the nasopharyngeal microbiome by 16S sequencing, and the resistome by shotgun sequencing. The researchers are developing a novel bait-enriched targeted pull-down method to identify AMR M. haemolytica in the DNA isolated from nasopharyngeal swabs for microbiome and resistome assessment. This work, which will continue in the new proposed project, will help veterinarians and farmers make decisions to support cattle health with the least possible pressure to expand antimicrobial resistance. 14. Researcher from AU in collaboration with MS are determining the effects of maternal vaccination and vaccination of young calves on systemic and mucosal immune responses and resistance to BRSV challenge in calves at weaning. Calves from dams vaccinated in late gestation vs not, or calves vaccinated in the first week of life vs not, are sampled at various time points between birth and weaning for measurement of serum and nasal antibodies directed against BRSV. Calves are experimentally challenged post weaning with BRSV, and serum and nasal secretions are collected at various time points post challenge. The results will help veterinarians and cattle producers make more informed decisions when developing vaccine protocols to keep calves healthy. 15. A research project completed by collaboration among SD, MS and IA to examine mucosal immunity following parenteral vaccination and challenge against BRSV. Calves were vaccinated at approximately 1 month of age and challenged ~90 days later when BRSV systemic antibodies were <1:4. Body temperature and other clinical signs were lower in the vaccinates. Nasal viral shed was 3–4 times lower in the vaccinated animals compared to the controls. On day 8 following challenge, animals were necropsied, and lung lobes were scored and tested for virus by PCR and indirect fluorescent assay (IFA). Only 29.4% of vaccinated calves were BRSV positive on IFA testing at necropsy, while 87.5% of control calves were BRSV positive. Vaccinated calves developed a mucosal BRSV IgA response with over 50% of the vaccinated calves having IgA prior to challenge and all vaccinated calves were positive following challenge. 16. In another study, inflammatory and humoral responses and adverse reactions induced by three adjuvanted commercial vaccines against BVDV and BHV-1 in Holstein heifers were examined by collaborative effort by SD, GA and Brazil. Thirty-five Holstein heifers (n = 35) were randomly assigned to four groups by adjuvant compounds: Vaccine A (Alum; n = 9), Vaccine B (Oil-in-water; n = 10), Vaccine C (Amphigen/Quil A cholesterol and dimethyl-dioctadecyl ammonium (DDA) bromide (QAD; n = 10), and Control (n = 6). Vaccine containing mineral oil or Amphigen/QAD presented greater local reactivity and induced a significant systemic inflammatory response. Vaccinated heifers with Alum and Amphigen/QAD commercial vaccines enhanced humoral immune response against BVDV and BHV-1. 17. A research project (Collaboration between SD and OK) to perform complete genome sequence of the first two bovine isolates BHV-1.1 LA strain and Cooper strain from the 1950’s and six wild-type BHV-1.1 isolates were compared. The Cooper strain is the major strain in almost all US BHV-1 vaccines. A nucleotide sequence divergence of 0.74% was noted across the two complete genomes, caused by 19 singlenucleotide polymorphisms (SNPs) involving 12 genes and insertions/deletions that primarily affected the number of repeats within reiterated repeat regions of the genome. Phylogenetic analysis revealed that Cooper and LA strains are genetically the most ancient strains from which all of the more-recently isolated field strains of BoHV-1.1 evolved. 18. A dual challenge model using BVDV 1b and M. hemolytica was developed by collaboration between SD and OK. This model resulted in excellent lung pathology and was used in a comparative vaccine efficacy with four different vaccine combinations. 19. The immune response following subcutaneous or intranasal modified-live virus booster vaccination against bovine respiratory disease in pre-weaning beef calves was compared in a study performed by GA in collaboration with MS. Booster vaccination of young beef calves using either SC or IN route two months after IN MLV primary vaccination resulted in comparable SNA titers, cytokine gene expression profile and virus-specific IgA concentration in nasal secretions. Only a few differences in the systemic and mucosal immune response against BHV1 and BRSV were observed between vaccinated groups. 20. Research done by collaboration between KS, SD and the PAC Group to determine the effects of cattle handling intensity at processing on physiological, inflammatory, and immune stress markers in newly received feeder calves. The results demonstrated that aggressive handling causes negative physiological and inflammation responses in newly received beef cattle. 21. 2019 BRD Symposium: CA, GA, KS, IA, OK, SD, WI, and MS assisted in organizing and delivering the 3rd BRD Symposium presented by NC1192, which was held on August 7-8 2019 in Denver CO in conjunction with the Summer Academy of Veterinary Consultants (AVC) meeting. Over 200 veterinarians and scientists from the U.S., Canada, and other countries attended. Many positive comments were received by the organizing committee regarding the information presented at the symposium, and we are planning to hold the 4th BRD Symposium in 2024. The proceedings will be published in a special issue of the journal Animal Health Research Reviews (AHRR) in December 2020. After the papers are published in AHRR they will be available on the BRD Symposium website (www.brdsymposium.org). GA has established strategic collaborative relationships with research institutions in Argentina (CONICET-INTA) through the USA Fulbright Scholar program. In addition, continuing education programs have been established with faculty at University of Sao Paulo (USP) in Brazil in the area of neonatal immune development and protection against BRD and other pathogens under funding from FAPESP, and collaborative studies on the impact of intranasal vaccine in dairy cattle relative to parturition between US and Australia on development of nasal secretion biomarkers. 22. Researchers from CA, WI and OK plan to resubmit a USDA proposal to expand and validate the BRD risk assessment tool developed by UC Davis to incorporate the epidemiology of BRD specific to management and climate practices in these states.

Objectives

1. To elucidate pathways by which host characteristics, pathogen virulence mechanisms, and environmental impacts interact to produce BRD.
   
2. To develop and validate methodologies for accurate BRD diagnosis, comprehensive and objective risk assessment, and surveillance to detect new patterns in BRD occurrence.
   
3. To develop and validate management practices and responsibly applied therapeutic and preventative interventions, such as vaccines, antimicrobials, and immunomodulators, to minimize the impact of BRD on cattle, producers, and society.
   
4. To determine how attributes of cattle production systems including epidemiologic, societal, and economic forces contribute to BRD, and to develop ways to promote changes in those systems to reduce the occurrence of BRD and improve cattle health, welfare, productivity and antimicrobial stewardship.
   
5. To promote dialogue and exchange among scientists, veterinarians, allied industry professionals and cattle producers to advance BRD research initiatives, to implement outreach, to disseminate research results, and to facilitate the translation of research findings to practical field applications.
   
6. To assess the economic impact of BRD across different sectors of cattle industry.
   

Methods

Throughout the methods, we have bolded collaborative efforts and institutional identification, as the overarching goal of the NC 1192 Multi-state project is to produce highly multi-disciplinary, multi-institutional research and extension outputs. 

 Objective 1: To elucidate pathways by which host characteristics, pathogen virulence mechanisms, and environmental impacts interact to produce BRD.

In effort to elucidate pathways by which host characteristics, pathogen virulence mechanisms, and environmental impacts interact to produce BRD, research groups from South Dakota (SD), Wisconsin (WI), Kansas (KS), Auburn (AU), Mississippi (MS), and Georgia (GA) have planned research in the next 5 years.

SD plans to focus on the role of BVDV in BRD. BVDV results in immune dysfunction enhancing bovine respiratory disease. This dysfunction begins with macrophages and their interaction with lymphocyte and neutrophils. South Dakota is working with NADC to do mass spectrometer analysis of BVDV-infected macrophages to identity these cellular factors associated with lymphocyte depletion and neutrophil activation. In cooperation with WI, SD is beginning assays with macrophage supernatants to determine their effect on activation of neutrophil.

In addition, Bovine rhinitis virus (BRV) is an established, albeit largely forgotten, causative agent of BRD. Numerous recent viral metagenomic surveys of cattle with bovine respiratory disease (BRD) have identified BRV in acute samples, with detection significantly associated with disease in several publications. SD is collaborating with KS to investigate the role of BRV in relation to BRD. An isolate of bovine rhinitis B virus was cultured from a BRD outbreak on primary bovine tracheal cells and will be used to evaluate the pathogenesis of BRBV in a colostrum-deprived calf model. Companion diagnostic tests including RT-PCR, serology and immunohistochemistry are being developed to support the pathogenesis trial. Additionally, Investigation of the incidence of BRV in BRD diagnostic submissions is being conducted with collaborators at Kansas State (KS) University Veterinary Diagnostic Laboratory. Longitudinal studies evaluating virus shedding and serology are being conducted with collaborators at USDA-MARC.

Researchers at AU and MS aim to understand the pathophysiology, immune response, and clinical protection offered by vaccination against viral respiratory pathogens. Pathogens of impact include bovine viral diarrhea virus (BVDV), infectious bovine rhinotracheitis (IBR), and bovine respiratory syncytial virus (BRSV). The evaluation of each one of these components relies on strict experimental virus-challenge models that allow collection of data from different sampling methodologies.

Researchers GA will work with partners at AU to determine lymphoid tissue transcriptomics of beef calves experimentally challenged with Bovine viral Diarrhea Virus of different sub-genotypes and virulence. The aim is to identify gene products that characterize the early immune response of calves infected with BVDV of low and high virulence in order to identify pathways of immunosuppression associated with BVDV virulence and disease severity.

MS and TX, in collaboration with others, will study how commingling of dairy cattle affects the composition of the respiratory and induces changes in the host immune and inflammatory response, and how these changes are related to shedding of respiratory coronavirus (BoCV). This collaboration will lead to the generation of comprehensive datasets related to pathogen behavior, host immuno-inflammatory responses, and microbiome dynamics during commingling events, to generate an epidemiological risk factor model for clinical disease following commingling.

MS and TX will determine how preweaning vaccination and postweaning commingling impact the host inflammatory response, and how the host inflammatory response is related to risk of disease and outcome following disease during the postweaning period in beef cattle.

Objective 2: To develop and validate methodologies for accurate BRD diagnosis, comprehensive and objective risk assessment, and surveillance to detect new patterns in BRD occurrence.

Researchers from Nebraska (NE), SD, TN, and MS plan to develop and validate methodologies for accurate BRD diagnosis, objective risk assessment, and surveillance to detect new patterns in BRD occurrence.

New pathogens and remerging pathogens are important in BRD pathogenesis. NE and SD are using Next Generation Sequencing to investigate pathogen patterns in cattle with BRD. Additional multiplex PCR panels for BRD pathogens will be developed to speed diagnostics. South Dakota continually monitors pathogen diagnostics and shares that with all stations and provides isolates to all stations that request them.

Secondly, SD Animal Disease Research and Diagnostic Laboratory recently began offering viral metagenomic sequencing as a diagnostic test. MS will collaborate with SD to assess the respiratory virome in high risk stocker cattle. Applied to BRD samples, this technology is uniquely positioned to identify both established and novel or emerging viruses associated with disease. SDSU has already analyzed ~50 BRD samples using this method and has identified a number of potential viral pathogens that may play a role in the etiology of BRD. SD will continue to perform this testing and compile and publish results from this diagnostic testing. Candidate emerging viruses with potential causative roles in BRD will be further studied. Follow up studies include virus isolation and pathogenesis in colostrum deprived calves. Demonstration of pathogenicity will warrant further vaccine development studies.

TN investigators will work in collaboration with MS teams to evaluate the usefulness of remote monitoring of BRD clinical signs for accuracy and timely diagnosis in high risk stocker cattle. Specific monitoring will include utilization of near-real time activity monitoring, body temperature, and heart rate data. In addition to this trial, precision feeding and watering technologies will be utilized to determine ability to detect behavioral changes in early BRD onset.

MS and TX will collaborate to develop a novel bait-enriched targeted pulldown method to identify the bacterial BRD agent Mannheimia haemolytica in microbiomes generated by 16S sequencing or shotgun sequencing, in order to increase sensitivity of identification of M. haemolytica in microbiomes. They will then compare the sensitivity of the pulldown method to traditional quantitative PCR (qPCR) methodology to identify antimicrobial resistant M. haemolytica in the nasopharynx of cattle at risk for BRD.

MS and TX will compare methods for identification of BRD agents: nasal swabs, non-guarded nasopharyngeal swabbing, and guarded nasopharyngeal swabbing, to determine the rate at which each method identifies M. haemolytica in cattle at risk for BRD, or with BRD. This will help to determine whether the current standard, guarded nasopharyngeal swabbing, which is expensive and generates more plastic waste, is necessary.

CA, WI and OK researchers plan to resubmit a proposal to USDA NIFA to expand and validate the BRD risk assessment tool developed by UC Davis and incorporate the epidemiology of BRD specific to other management practices in these states. The proposed research will evaluate use of a risk assessment approach on reducing the risk of BRD in preweaned dairy calves. In addition, the risk assessment will be implemented as a native mobile application that can be used by producers, veterinarians and professionals concerned with BRD in dairy calves.

Objective 3: To develop and validate management practices and responsibly applied therapeutic and preventative interventions, such as vaccines, antimicrobials, and immunomodulators, to minimize the impact of BRD on cattle, producers, and society.

Investigators in KS, SD, MS, IA, GA, and NE plan research projects aimed to develop and validate management practices and responsibly applied therapeutic and preventative interventions, such as vaccines, antimicrobials, and immunomodulators, to minimize the impact of BRD on cattle, producers, and society.

 In collaboration with KS, SD will work to evaluate next generation mosaic vaccines for BRD. Currently, SD and MS are involved in project determining the preventative and therapeutic uses of interferon lambda for BRD. In collaboration with MS and IA, SD researchers aim to evaluate the effectiveness of secretory IgG produced by parenteral vaccines.

Researchers at GA will work alongside AU to assess redistribution of T cell populations in lymphoid tissues after acute coinfection of BVDV2 and BHV1 in dairy calves immunized with MLV vaccines and supplemented with trace minerals (TM). Researchers at UGA will determine the abundance and distribution of activated T cell populations in lymphoid tissues and respiratory tract mucosa during acute infection with BVDV-2 and BHV-1. They hypothesized that calves that received booster MLV vaccination along with TM supplementation will have a significantly greater number of T cell populations (singles: CD4 , CD8 , WC1 , CD25 ) and activated phenotypes (doubles: CD4 CD25 , CD8 CD25 , and WC1 CD25 ) in lymphoid tissues and respiratory mucosa/submucosa. They also hypothesized that the number of lymphocytes expressing memory (CD45 RA ) and homing markers (CD62L ) on lymphoid and upper respiratory tract tissues would be affected by the vaccination route and trace mineral injection.

In collaboration with MS, GA plans to perform transcriptomic analysis of respiratory mucosa and lymphoid tissue of dairy calves co-infected with BVDV + BHV1. The aim is to identify differentially expressed genes that characterize the early immune response of calves co-infected with BVDV2 and BHV1, as well as protection elicited by different MLV vaccination routes. The goal is to elucidate immunological mechanisms involved in acute viral co-infections and vaccine protection.

MS and TX will collaborate to develop a novel bait-enriched targeted pulldown method to identify the bacterial BRD agent Mannheimia haemolytica in microbiomes generated by 16S sequencing or shotgun sequencing, in order to increase sensitivity of identification of M. haemolytica in microbiomes. They will then compare the sensitivity of the pulldown method to traditional quantitative PCR (qPCR) methodology to identify antimicrobial resistant M. haemolytica in the nasopharynx of cattle at risk for BRD.

MS and TX will compare methods for identification of BRD agents: nasal swabs, non-guarded nasopharyngeal swabbing, and guarded nasopharyngeal swabbing, to determine the rate at which each method identifies M. haemolytica in cattle at risk for BRD, or with BRD. This will help to determine whether the current standard, guarded nasopharyngeal swabbing, which is expensive and generates more plastic waste, is necessary.

Objective 4: To determine how attributes of cattle production systems including epidemiologic, societal, and economic forces contribute to BRD, and to develop ways to promote changes in those systems to reduce the occurrence of BRD and improve cattle health, welfare, productivity and antimicrobial stewardship.

SD, GA, MS, TX, NE, and TN researchers plan to determine how attributes of cattle production systems including epidemiologic, societal, and economic forces contribute to BRD, and to develop ways to promote changes in those systems to reduce the occurrence of BRD and improve cattle health, welfare, productivity, and antimicrobial stewardship.

MS and TX have active research on stress and nutrition on arrival impacting BRD.  This is also an active area of BRD research for SD investigators with potential for collaboration. SD has been working on interventions with probiotics and prebiotics in a system by identifying benchmark biomarkers using heat stress as the stressor.

There are long-term ongoing investigations into pre-weaning beef calf pneumonia cases. Collaborators are from MS, GA, NE, and TX. These investigations will continue and will determine epidemiological contributors to BRD in beef cow-calf systems.

Investigators in TN will work with others at MS to survey beef cattle producers at Cattlemen’s meetings and auction markets to determine the impacts that pre-weaning management and marketing decisions have on BRD risk during the stockering phase.

MS, in collaboration with KS and TX, will determine how preweaning vaccination and postweaning transport through an auction market and order buyer facility impacts the rate and severity of BRD in post-weaned beef calves during the backgrounding period. The group will also assess the epidemiologic characteristics of lots of feedlot cattle that develop BRD at various rates and severities. This work is needed because, while preweaning vaccination and postweaning commingling are widely understood to impact BRD risk, there are few data from controlled research to allow these effects to be objectively quantified.

MS and TX will assess the impact of on-arrival antimicrobial metaphylaxis (mass medication) on the prevalence of antimicrobial resistance in M. haemolytica, and on the prevalence of genes encoding antimicrobial resistance in the respiratory microbiome of beef stocker cattle at various time points post arrival.

Objective 5: To promote dialogue and exchange among scientists, veterinarians, allied industry professionals and cattle producers to advance BRD research initiatives, to implement outreach, to disseminate research results, and to facilitate the translation of research findings to practical field applications.

Researchers in SD, MS, MI, AL, Arkansas (AR), AU, and Louisiana (LA) plan to promote dialogue and exchange among scientists, veterinarians, allied industry professionals and cattle producers to advance BRD research initiatives, to implement outreach, to disseminate research results, and to facilitate the translation of research findings to practical field applications.

All stations will actively participate with other stations in the planning and delivery of the 2024 BRD Symposium. The BRD Symposium, which this Multi-State Project has delivered every 5 years since 2009, provides an opportunity for veterinarians, researchers, producers, members from the pharmacologic and biologics industry, and policy makers to come together regular to learn about new developments in methods to control and prevent BRD, and to plan research and other collaborative activities to further knowledge and practices needed to control and prevent BRD. SD will also participate with the other stations in the development of publications for AABP, Animal Health Research and Reviews and Clinics of North America- Food Animal. SD along with MS, MI, and AL in the production of a textbook on Bovine Immunology that includes major sections on BRD pathogens and risk factors associated with BRD. SD along with KS, NE, and MS will contribute to a revised Veterinary Microbiology book that will contain extensive information on BRD pathogens.

Working closely with AR, AU, and MS, LA researchers plan to incorporate findings from all other Objectives into extension programs for beef and dairy producers, including the Beef Quality Assurance Certification program and Master Cattlemen programs. Findings will also be incorporated into continuing education courses for veterinarians.

Extensionists from FL in collaboration with GA researchers are planning to develop a workshop on 2021-2022 for producers and veterinarians about “Vaccines and Vaccinations” for control respiratory and reproductive disease in cattle.

The results of the economic impact of BRD in dairy and beef industries, as well as the economic impact of preventive strategies, will be shared with producers, veterinarians, and extension advisors during the extension activities proposed. Economic results will provide information to help stakeholders to make better informed decisions towards preventing BRD.

Objective 6: To assess the economic impact of BRD across different sectors of cattle industry.

CA, TN, and MS researchers plan to collaborate to assess the economic impact of BRD across different sectors of cattle industry.

Past research has shown that economic information helps farmers to make better informed decisions, and current literature on the economics of BRD is fragmented by sector of the cattle industry in the US. Therefore, researchers in CA, TN, and MS plan to measure the current economic impact of BRD on both the US dairy and beef industries, and the impacts that current and proposed preventive measures have when incidence of BRD is reduced.

CA, TN, and MS will use an epidemiological and productivity model to combine and extend on the most up-to-date literature of the economics of BRD in the US. We will simulate different scenarios of reduction of BRD incidence in dairy and beef herds using current and proposed preventive approaches. The costs and potential production impacts of the strategies will be modeled, and the economic impacts of reducing the incidence of BRD in both dairy and beef industries will be measured. Data from literature and US market will be used as inputs for the epidemiological and economic models. Sensitivity analysis will be performed by varying the input costs and outcomes achieved when preventive measures are implemented. The economic results will be used to inform the dairy and beef industries across the US in collaboration with researchers in SD, MS, MI, AR, AU, LA, and FL. This information will help farmers to make better informed decisions when implementing preventive measures for BRD.

 

 

Measurement of Progress and Results

Outputs

• Improved basic knowledge of host characteristics, pathogen virulence mechanisms, and environmental factors that contribute to the development of BRD.
• Generate information on new pathogens isolated from animals with respiratory disease and models to assess their role in BRD pathogenesis.
• Assays, scoring systems, biometric measurements, and models that accurately detect and diagnose BRD (both clinically and etiologically) in production settings.
• Prevention strategies, including management practices, vaccines and vaccination protocols, and therapeutic technologies that effectively decrease the incidence and impact of BRD.
• Models that describe how and why cattle are managed in ways that either prevent or predispose cattle to developing BRD as well as new strategies to encourage producer adoption of techniques and technologies that reduce BRD incidence and impact.
• Peer-reviewed articles, lay articles, posters, presentations, webinars, workshops, and symposia to communicate the results of research conducted by members of NC-1192.
• Grant proposals to federal agencies from multi-disciplinary and multi- institutional teams.

Outcomes or Projected Impacts

• 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
• Researchers in academic, government, and industry laboratories will be provided with basic foundational and applied information regarding BRD that will be necessary for their ongoing work to advance scientific discovery in the fields of vaccinology, immunology, microbiology, pharmacology, and animal husbandry
• Scientists, veterinarians, and policy makers working to maximize judicious 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
• 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
• 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

Milestones

(2):Objective 1: MS and TX will initiate a project that will lead to an epidemiological risk factor model for bovine coronavirus infection in comingled dairy cattle. MS and TX will determine the impact of vaccination and commingling on host inflammatory responses in beef cattle. AL and GA will initiate a project investigating early immune response of calves infected with BVDV.

(2):Objective 2: Researchers from SD, MS, TN and TX will develop methodologies for BRD diagnosis and surveillance. TX and MS will develop a novel bait-enriched pulldown method to allow specific identification and whole genome sequencing of bacterial BRD pathogens in metagenomes. CA, WI and OK researchers to develop the next BRD risk assessment that expands to other US regions to capture different management and climate factors.

(3):Objective 3: Researchers from IA, MS and SD will evaluate production of secretory IgG following vaccination. MS and TX will initiate a project to compare nasal and nasopharyngeal swabbing techniques for diagnosis of bacterial BRD pathogens. AU and MS will determine the relative impact of maternal or calfhood vaccination on mucosal IgA and IgG production before and after viral respiratory infection of calves.

(3):Objective 4: KS, MS and TX will quantify the rate and severity of BRD following postweaning comingling, with or without preweaning respiratory vaccination, in beef calves. MS and TX will determine the prevalence of phenotypic antimicrobial resistance, and the prevalence of mobile genetic elements encoding antimicrobial resistance, following metaphylactic antimicrobial administration to high risk beef cattle at arrival.

(3):Objective 5: All stations will meet annually to report relevant findings and spend time developing multi-institutional research objectives and projects for the upcoming year. All stations will plan and deliver the 4th BRD symposium to be held in 2024. A quarterly webinar will be initiated to expand outreach and collaboration of the group.

(3):Objective 6: CA, TN, and MS plan to measure the economic impact of BRD in the beef and dairy industry.

Projected Participation

View Appendix E: Participation

Outreach Plan

 Basic information generated will be disseminated through peer-reviewed journals. Members of NC-1192 have a tremendous history of publishing their work in peer-reviewed journals, thus helping to advance the science of BRD globally. Just as importantly, NC-1192 team members have actively been involved in contributing to the lay literature. Dissemination of information at the applied level will continues through lay publications will continue to be a focus of this project

Annual presentations by team members at annual meetings of the AAVLD-USAHA, CRWAD, AABP and AVC (and others) will aid in the dissemination of information to veterinarians, cattle producers, and researchers, as well as technology transfer of the latest validated diagnostic methods to US veterinary diagnostic laboratory network.

NC-1192 will continue to create dialog surrounding BRD by engaging the industry at various levels. The primary point of engagement will be involvement with national organizations including the USDA, AABP, AVC and NCBA. This will be accomplished by actively participating in and creating open dialog opportunities with these organizations. As a culmination of these efforts, the 4th BRD Symposium will be planned and held during the course of the project. The BRD Symposium has been hosted by NC-1192 every 5 years since 2009 and reaches a broad range of stakeholders including producers, veterinarians, researchers and policy makers.

To increase NC-1192’s impact and promote collaboration between researchers a quarterly webinar will be hosted NC-1192 member station Iowa State University. The webinar will be promoted to allied organizations and stakeholders such as AABP, AVC, NCBA and others. One section of the webinar will disseminate current research findings to participants and the other section will facilitate dialog between NC-1192 members to enhance collaboration.

Organization/Governance

The Technical Committee will consist of one voting member from each cooperating station as appointed or otherwise designated by that station, with an Administrative Advisor. A President and Secretary of the Technical Committee will be elected by a majority vote of the committee; each will serve a one-year term. Annual meetings will be held at a time and site agreed on by the Technical Committee, with the majority of meetings held in conjunction with a national meeting of an organization related to bovine health (such as the American Association of Bovine Practitioners or the Academy of Veterinary Consultants). At the annual meeting, the Secretary will record the minutes and submit them to the Technical Committee for approval. The President and Secretary will prepare the annual report summarizing material supplied by the voting member from each participating station and, following approval of the report by the Technical Committee, will submit the report to the Administrative Advisor for dissemination to the appropriate parties.

Literature Cited

Bassel LL et al. Host tolerance to infection with the bacteria that cause bovine respiratory disease. Vet Clin North Am Food Anim Pract, 36 (2020), pp. 349-359.

Chamorro MF and Palomares RA. Bovine respiratory disease vaccination against viral pathogens: modified-live versus inactivated antigen vaccines, intranasal versus parenteral, what is the evidence? Vet Clin North Am Food Anim Pract, 36 (2020), pp. 461-472.

Fulton RW. Viruses in bovine respiratory disease in North America: knowledge advances using genomic testing. Vet Clin North Am Food Anim Pract, 36 (2020), pp. 321-332.

Ishmael W. Gasping for dollars. Angus Beef Bulletin. Angus Productions Inc., St. Joseph MO. (2001).

Maier GU et al. Development of a clinical scoring system for bovine respiratory disease in weaned dairy calves. J Dairy Sci, 102 (2019), pp. 7329-7344. doi: 10.3168/jds.2018-15474

Peel DS. The effect of market forces on bovine respiratory disease. Vet Clin North Am Food Anim Pract, 36 (2020), pp. 497-508.

Scott MA et al. Whole blood transcriptomic analysis of beef cattle at arrival identifies potential predictive molecules and mechanisms that indicate animals that naturally resist bovine respiratory disease. PLOS One, 15:e0227507. (2020). https://doi.org/10.1371/journal.pone. 0227507

Shirbroun R. Histophilus somni: antigenic and genomic changes relevant to bovine respiratory disease. Vet Clin North Am Food Anim Pract, 36 (2020), pp. 279-295.

USDA. Beef 2007-08 Part IV: Reference of Beef Cow-Calf Management Practices in the United States, 2007-08, USDA-APHIS- VS-CEAH-NAHMS. (2010).

USDA. Feedlot 2011 Part IV: Health and Health Management on U.S. Feedlots with a Capacity of 1,000 or More Head, USDA-APHIS-VS-CEAH-NAHMS. (2013).

USDA. Death Loss in U.S. Cattle and Calves Due to Predator and Nonpredator Causes, 2015. USDA-APHIS-VS-CEAH-NAHMS. (2017).

USDA. Dairy 2014 Health and Management Practices on U.S. Dairy Operations, 2014. Report 3. USDA-APHIS-VS-CEAH-NAHMS. (2018).

Attachments

Land Grant Participating States/Institutions

AL, CA, GA, KS, LA, MS, TN, TX, WA, WI

Non Land Grant Participating States/Institutions

Iowa State University - College of Vet Med, Mississippi State University, USDA-ARS/NE