Pathogenesis, Host Innate Immune Response, and Aerosol Transmission of Influenza D Virus in Cattle.

The recently discovered influenza D virus (IDV) of the Orthomyxoviridae family has been detected in swine and ruminants with a worldwide distribution. Cattle are considered to be the primary host and reservoir, and previous studies suggested a tropism of IDV for the upper respiratory tract and a putative role in the bovine respiratory disease complex. This study aimed to characterize the pathogenicity of IDV in naive calves as well as the ability of this virus to transmit by air. Eight naive calves were infected by aerosol with a recent French isolate, D/bovine/France/5920/2014. Results show that IDV replicates not only in the upper respiratory tract but also in the lower respiratory tract (LRT), inducing moderate bronchopneumonia with restricted lesions of interstitial pneumonia. Inoculation was followed by IDV-specific IgG1 production as early as 10 days postchallenge and likely both Th1 and Th2 responses. Study of the innate immune response in the LRT of IDV-infected calves indicated the overexpression of pathogen recognition receptors and of chemokines CCL2, CCL3, and CCL4, but without overexpression of genes involved in the type I interferon pathway. Finally, virological examination of three aerosol-sentinel animals, housed 3 m apart from inoculated calves (and thus subject to infection by aerosol transmission), and IDV detection in air samples collected in different areas showed that IDV can be airborne transmitted and infect naive contact calves on short distances. This study suggests that IDV is a respiratory virus with moderate pathogenicity and probably a high level of transmission. It consequently can be considered predisposing to or a cofactor of respiratory disease.IMPORTANCE Influenza D virus (IDV), a new genus of the Orthomyxoviridae family, has a broad geographical distribution and can infect several animal species. Cattle are so far considered the primary host for IDV, but the pathogenicity and the prevalence of this virus are still unclear. We demonstrated that under experimental conditions (in a controlled environment and in the absence of coinfecting pathogens), IDV is able to cause mild to moderate disease and targets both the upper and lower respiratory tracts. The virus can transmit by direct as well as aerosol contacts. While this study evidenced overexpression of pathogen recognition receptors and chemokines in the lower respiratory tract, IDV-specific IgG1 production as early as 10 days postchallenge, and likely both Th1 and Th2 responses, further studies are warranted to better understand the immune responses triggered by IDV and its role as part of the bovine respiratory disease complex.

Field trial to evaluate the effect of an intranasal respiratory vaccine protocol on bovine respiratory disease incidence and growth in a commercial calf rearing unit.

BACKGROUND: Bovine respiratory disease (BRD) continues to be great challenge in calf rearing units. The urgent need to decrease the use of antibiotics and increase animal welfare in beef production has forced us to introduce new preventive methods. Vaccinations could contribute to the solution, but the high incidence of BRD already at an early age has made it difficult to introduce suitable vaccination programs. Challenge studies have shown promising results in 3-14 day old calves vaccinated with intranasal BRD vaccine, but very few field trials are available to assess the efficacy of the intranasal vaccines in field conditions. We evaluated the effect of one dose of commercial intranasal vaccination on calf mortality, daily gain, and treatment incidence for BRD in one calf rearing unit. In total, 497 calves (mean age 19 days) were included in our study, 247 of which were vaccinated at the time of arrival to the unit and 250 served as negative controls (unvaccinated). Vaccinated and unvaccinated calves were situated in separate compartments until weaning. Daily gain, treatment incidence, and mortality were recorded until the calves were transported to the finishing unit, which averaged 154.5 days from arrival. RESULTS: Average daily gain over the complete study period was 1151.9 g/day (SD 137.9) for the vaccinated calves and 1139.5 g/day (SD 135.9) for the unvaccinated calves. Intranasal vaccination combined with older arrival age (17 days or older) resulted in a higher daily gain (47.8 g/day) compared with unvaccinated calves (coef. 0.0478, p = 0.003). This association was not recorded in calves that were younger than 17 days upon arrival. Intranasal vaccination was not significantly associated either with mortality (OR 0.976, p = 0.968) or treatment incidence for BRD (OR 1.341, p = 0.120). In total, six vaccinated calves (2.43%) and six unvaccinated calves (2.40%) died during the study period. CONCLUSIONS: Vaccinating arriving calves with intranasal vaccine in the calf rearing unit did not decrease the mortality or treatment incidence for BRD, but it significantly improved the weight gain in calves transported to the unit at the age of 17 days or older.

Investigation of the safety and protective efficacy of an attenuated and marker M. bovis-BoHV-1 combined vaccine in bovines.

Bovine respiratory disease (BRD) is one of the most common diseases in the cattle industry worldwide; it is caused by multiple bacterial or viral coinfections, of which Mycoplasma bovis (M. bovis) and bovine herpesvirus type 1 (BoHV-1) are the most notable pathogens. Although live vaccines have demonstrated better efficacy against BRD induced by both pathogens, there are no combined live and marker vaccines. Therefore, we developed an attenuated and marker M. bovis-BoHV-1 combined vaccine based on the M. bovis HB150 and BoHV-1 gG-/tk- strain previously constructed in our lab and evaluated in rabbits. This study aimed to further evaluate its safety and protective efficacy in cattle using different antigen ratios. After immunization, all vaccinated cattle had a normal rectal temperature and mental status without respiratory symptoms. CD4+, CD8+, and CD19+ cells significantly increased in immunized cattle and induced higher humoral and cellular immune responses, and the expression of key cytokines such as IL-4, IL-12, TNF-α, and IFN-γ can be promoted after vaccination. The 1.0 × 108 CFU of M. bovis HB150 and 1.0 × 106 TCID50 BoHV-1 gG-/tk- combined strain elicited the most antibodies while significantly increasing IgG and cellular immunity after challenge. In conclusion, the M. bovis HB150 and BoHV-1 gG-/tk- combined strain was clinically safe and protective in calves; the mix of 1.0 × 108 CFU of M. bovis HB150 and 1.0 × 106 TCID50 BoHV-1 gG-/tk- strain was most promising due to its low amount of shedding and highest humoral and cellular immune responses compared with others. This study introduces an M. bovis-BoHV-1 combined vaccine for application in the cattle industry.

The effects of viral vaccination of dairy heifer calves on the incidence of respiratory disease, mortality, and growth.

Bovine respiratory disease (BRD) is one of the most common infectious causes of morbidity and mortality in young dairy cattle. The objective of this randomized clinical trial was to determine the effectiveness of 1 or 2 doses of a 5-way, modified-live viral vaccine, administered to heifer calves before weaning to aid in the prevention of BRD. The hypotheses were that vaccination would reduce the incidence of BRD and mortality, and that 2 doses would be more effective than 1. A total of 2,874 heifer calves from 19 commercial dairy farms in Minnesota and Ontario were enrolled at 1 to 7d of age and were followed until 3 mo of age. Calves were randomly assigned to receive a commercial, intramuscular, modified-live vaccine against bovine viral diarrhea virus types 1 and 2, bovine respiratory syncytial virus, bovine herpesvirus type 1, and parainfluenza virus type 3 at 15 to 21 d of age (2 wk only), 35 to 42 d (5 wk only), both 2 and 5 wk, or sterile saline at both times (unvaccinated controls). The incidence of failure of passive transfer was 11 or 32%, using cut-points of serum total protein of 5.2 and 5.7 g/dL, respectively. Overall, 22% of calves were treated at least once for BRD. The incidence risk of naturally occurring BRD was 7.7% before 2 wk of age, 8.0% between 2 and 5 wk, and 9.5% between 5 wk and 3 mo of age, and was not different between vaccination groups. Overall mortality throughout the 3-mo study period was 3.5%. Mortality was 1.6% before 2 wk of age, 0.5% between 2 and 5 wk, and 1.2% between 5 wk and 3 mo of age. The risk of mortality was not affected by vaccination. Mean average daily gain of 1.07 kg/d from 5 wk to 3 mo of age was not different between vaccine groups. In this population of commercial, home-raised calves, with an overall low incidence of failure of passive transfer, intramuscular vaccination with a multivalent, modified live viral vaccine at 2 or 5 wk of age or both was not associated with a decreased risk of BRD or mortality, or with growth until 3 mo of age. Reasons for these findings may include interference by maternal antibodies, unresponsiveness of the neonatal immune system, timing of immunity relative to pathogen exposure, disease caused by pathogens other than the viruses in the vaccine, or herd immunity. However, in populations with higher incidence of failure of passive transfer or risk of BRD, calves with low levels of specific antibodies may respond differently to vaccination.

Association of single nucleotide polymorphisms in the ANKRA2 and CD180 genes with bovine respiratory disease and presence of Mycobacterium avium subsp. paratuberculosis(1).

The objective was to determine whether single nucleotide polymorphisms (SNPs) in the ANKRA2 and CD180 genes are associated with incidence of bovine respiratory disease (BRD) and presence of Mycobacterium avium subsp. paratuberculosis (MAP) in cattle. Two independent populations were used. The first population (BRD-affected; N = 90) was composed of 31 half-sib progeny, from a Brahman × Angus sire, that were treated for BRD. Untreated offspring from the sire were selected to serve as controls. The second population (MAP-infected) of 330 animals of unknown parentage was evaluated for the presence of MAP in ileocecal lymph node and classified as positive or negative. Markers in both genes were assessed for association in these two populations. In the BRD-affected population, five SNPs in the ANKRA2 gene were significantly associated (P < 0.05), and two SNPs were highly associated (P < 0.01) with incidence of BRD. In addition, two SNPs in the CD180 gene were found to be associated with this trait. In the MAP-infected population, one SNP in the ANKRA2 gene was significantly associated (P < 0.05) with the presence or absence of MAP, and a SNP in the CD180 gene was highly associated (P < 0.01) with the trait. Haplotypes, using significant markers, showed a positive association with both incidence of BRD (P = 0.0001) and with the presence of MAP (P = 0.0032). Markers in the ANKRA2 and CD180 genes are associated with the ability of the animal to cope with pathogens.

Genes and regulatory mechanisms associated with experimentally-induced bovine respiratory disease identified using supervised machine learning methodology.

Bovine respiratory disease (BRD) is a multifactorial disease involving complex host immune interactions shaped by pathogenic agents and environmental factors. Advancements in RNA sequencing and associated analytical methods are improving our understanding of host response related to BRD pathophysiology. Supervised machine learning (ML) approaches present one such method for analyzing new and previously published transcriptome data to identify novel disease-associated genes and mechanisms. Our objective was to apply ML models to lung and immunological tissue datasets acquired from previous clinical BRD experiments to identify genes that classify disease with high accuracy. Raw mRNA sequencing reads from 151 bovine datasets (n = 123 BRD, n = 28 control) were downloaded from NCBI-GEO. Quality filtered reads were assembled in a HISAT2/Stringtie2 pipeline. Raw gene counts for ML analysis were normalized, transformed, and analyzed with MLSeq, utilizing six ML models. Cross-validation parameters (fivefold, repeated 10 times) were applied to 70% of the compiled datasets for ML model training and parameter tuning; optimized ML models were tested with the remaining 30%. Downstream analysis of significant genes identified by the top ML models, based on classification accuracy for each etiological association, was performed within WebGestalt and Reactome (FDR ≤ 0.05). Nearest shrunken centroid and Poisson linear discriminant analysis with power transformation models identified 154 and 195 significant genes for IBR and BRSV, respectively; from these genes, the two ML models discriminated IBR and BRSV with 100% accuracy compared to sham controls. Significant genes classified by the top ML models in IBR (154) and BRSV (195), but not BVDV (74), were related to type I interferon production and IL-8 secretion, specifically in lymphoid tissue and not homogenized lung tissue. Genes identified in Mannheimia haemolytica infections (97) were involved in activating classical and alternative pathways of complement. Novel findings, including expression of genes related to reduced mitochondrial oxygenation and ATP synthesis in consolidated lung tissue, were discovered. Genes identified in each analysis represent distinct genomic events relevant to understanding and predicting clinical BRD. Our analysis demonstrates the utility of ML with published datasets for discovering functional information to support the prediction and understanding of clinical BRD.

The Immunology of Bovine Respiratory Disease: Recent Advancements.

Bovine respiratory disease (BRD) remains a leading cause of morbidity, mortality, and economic loss to the cattle industry. The continued high prevalence of the disease underlines a gap in understanding of the host immune response to respiratory infection. The host immune response is beneficial and detrimental, required for clearing the disease but often leading to tissue damage and long-term defects in lung function. This article highlights advancements made in understanding innate and adaptive immunity in BRD, factors that predispose animals to BRD, and novel intervention strategies that may lead to changes in the approach to treating and controlling BRD.

Host Tolerance to Infection with the Bacteria that Cause Bovine Respiratory Disease.

Calves vary considerably in their pathologic and clinical responses to infection of the lung with bacteria. The reasons may include resistance to infection because of pre-existing immunity, development of effective immune responses, or infection with a minimally virulent bacterial strain. However, studies of natural disease and of experimental infections indicate that some calves develop only mild lung lesions and minimal clinical signs despite substantial numbers of pathogenic bacteria in the lung. This may represent "tolerance" to pulmonary infection because these calves are able to control their inflammatory responses or protect the lung from damage, without necessarily eliminating bacterial infection. Conversely, risk factors might predispose to bovine respiratory disease by triggering a loss of tolerance that results in a harmful inflammatory and tissue-damaging response to infection.

Pathogenesis and Virulence of Mycoplasma bovis.

Mycoplasma bovis is an important component of the bovine respiratory disease complex and recent reports identified that other species are also affected by M bovis. Control of the disease caused by M bovis has been unsuccessful owing to many factors, including the capacity of M bovis to evade and modulate the immune system of the host; the lack of known virulence factors; the absence of a cell wall, which renders antibiotics targeting cell-wall synthesis unusable; and the failure of vaccines to control disease on the field. The current knowledge on virulence and pathogenesis is presented in this review.

Histophilus somni: Antigenic and Genomic Changes Relevant to Bovine Respiratory Disease.

Histophilus somni is associated with several disease syndromes in cattle and plays an important role in the bovine respiratory disease complex. H somni isolates exhibit significant differences in terms of susceptibility to inactivation by normal serum corresponding to the general ability to cause clinical disease. Isolates possess a variety of virulence factors, and variation in virulence factor expression is well recognized and associated with antigenic differences. Sequencing of genes associated with known virulence factors has identified genetic variability between isolates. The antigenic and genomic differences represent significant challenges to the host immune system and are problematic for vaccine design.

Bovine Respiratory Disease Vaccination: What Is the Effect of Timing?

Vaccination is the act of administering a vaccine, whereas immunization may occur if appropriate time is allowed for a competent host immune system to respond to the antigen contained in a vaccine. Timing is critical to ensure bovine respiratory disease (BRD) vaccine safety, efficacy, and efficiency. The current review provides temporal considerations of BRD vaccination within the North American beef production system with focus on vaccination timing in high-risk, newly received beef stocker and feedlot cattle.

Bovine Respiratory Disease Vaccination Against Viral Pathogens: Modified-Live Versus Inactivated Antigen Vaccines, Intranasal Versus Parenteral, What Is the Evidence?

Vaccination of cattle against viral respiratory pathogens to minimize losses associated with bovine respiratory disease (BRD) is a common practice among producers and veterinarians. Three different calf populations in which BRD is most prevalent (recently weaned beef calves, preweaning beef calves, and young dairy calves) are the principal focus of morbidity and mortality prevention through vaccination; however, the evidence of vaccination efficacy is inconsistent in the literature. This review addresses the evidence of efficacy of vaccination in the prevention or reduction of naturally occurring and experimentally induced BRD in each calf group.

Association of plasma haptoglobin concentration and other biomarkers with bovine respiratory disease status in pre-weaned dairy calves.

We conducted a nested, case-control study of pre-weaned dairy calves ( n = 477; 4 California dairy farms) to assess the association between bovine respiratory disease (BRD) and hematologic biomarkers, including plasma haptoglobin (Hp) and plasma bactericide (PB). At each location, heifer or bull dairy calves were observed 2-4 times per week until confirmed as BRD-positive using parallel interpretation of thoracic ultrasound examination and auscultation. In addition, control calves were enrolled after being confirmed as BRD-negative using ultrasound and auscultation. Complete blood counts (CBC), PB, and Hp concentrations were measured. Hp values were higher in calves with confirmed BRD than in controls ( p < 0.01). The area under the curve (AUC) for the various biomarkers was obtained from the corresponding receiver operating characteristic curves. The AUC for Hp was 0.68, a value greater than those for PB or the remaining CBC parameters, indicating that Hp may be the most useful biomarker of BRD in pre-weaned dairy calves. The cutoff value for Hp was 0.195 g/L.

Effects of combined viral-bacterial challenge with or without supplementation of Saccharomyces cerevisiae boulardii strain CNCM I-1079 on immune upregulation and DMI in beef heifers.

Objectives were to determine whether live yeast (LY) supplementation would affect daily dry matter feed intake, body weight (BW), immune, and febrile responses to a viral-bacterial (VB) respiratory challenge. Crossbred heifers (N = 38, BW = 230 ± 16.4 kg) were allocated into a 2 × 2 factorial treatment arrangement: Factor 1 = roughage-based diet with or without LY (Saccharomyces cerevisiae boulardii CNCM I-1079, 62.5 g/hd/d), Factor 2 = VB, intranasal administration of bovine herpesvirus-1 (BHV-1, 2 ×108, PFU) on day 0 and endobronchial inoculation with Mannheimia haemolytica (5.4 × 1010, CFU) on day 3, or intranasal saline administration followed by inoculation with phosphate buffer solution (PBS). Heifers were fed their respective diets for 27 d prior to VB challenge on day 0. Heifers were housed by treatment and group-fed using electronic feedbunks. Thermo-boluses (Medria; Châteaubourg, FR) measured rumen temperature (RUT) at 5-min intervals and rectal temperature and whole blood samples were collected on days 0, 3 to 8, 10, 13, and 15. Data were analyzed using repeated measures in the mixed procedure of SAS with fixed effects of day, diet, inoculation, and their interactions. Animals fed LY exhibited a 16% increase (P = 0.02) in neutrophils relative to CON. Diet × inoculation × day interactions were detected for monocytes and haptoglobin. The VB-LY had the greatest (P < 0.05) concentration of monocytes on day 4, followed by VB-CON which was greater (P < 0.05) than PBS treatments. Haptoglobin concentration was greatest (P < 0.02) for VB-CON on day 5, followed by VB-LY which was greater (P < 0.05) than PBS. Heifers supplemented with LY had less (P < 0.05) haptoglobin production than CON. The VB challenge produced nasal lesions that increased (P < 0.01) with day, reaching a zenith on day 6 with 70% of the nares covered with plaques, and increased (P < 0.05) neutrophils on days 3 to 5. The VB challenge increased RUT (P < 0.05) days 2 to 7 and rectal temperature (P < 0.05) on days 0 and 3 to 6. The increased rectal temperature on day 0 was likely due to increased ambient temperature at time of challenge, as VB heifers were processed after the PBS heifers to avoid contamination. The VB challenge was effective at stimulating immune responses, and RUT was effective for measuring febrile responses. These results indicate that prior LY supplementation altered the leukogram in response to VB challenge, suggestive of increased innate immune response.

An immunomodulatory feed additive enhances in vitro viral vaccine recall antigen responses in dairy heifers.

Enhancing immunological responses to vaccination is an important goal in many herd health management systems. OmniGen-AF®(OG) is an immunomodulatory feed additive that has been shown to enhance innate immune function in ruminants and its effects on adaptive immunity require additional study. The objective of this study was to evaluate post-vaccine antibody titers and circulating cellular memory development in heifers fed OG and administered a commercially available modified-live bovine respiratory disease (BRD) vaccine. Twenty-four Holstein heifers were assigned to one of two diets for 170 days: Control TMR (CON; n = 11), or TMR plus OG (TRT; 9 g/100 kg BW/day; n = 13). Samples for hematology, serology, and cellular assays were collected on D-110, 0, 21, 42, and 60 of the trial. Heifers were administered two priming doses of a modified-live BRD vaccine, with a third dose given on D0. There were no significant differences in total WBC and absolute number or the percentage of circulating lymphocytes, monocytes, neutrophils, RBC, or platelets on D-110 through D21. On D42 and D60, CON had significantly higher numbers of lymphocytes. On D0, mean serum neutralizing (SN) titer to BHV-1 was significantly higher for CON compared to TRT. SN titers were not significantly different between CON and TRT at any other time point for BHV-1, BVDV type 1, or BVDV type 2. TRT mounted a significantly stronger recall proliferative response to 0.5 multiplicity of infection (MOI) of BHV-1, BVDV type 1 and BVDV type 2 on D42 and D60; 0.25 MOI of BVDV type 1 on D21 and D42; and 0.25 MOI BVDV type 2 on D42 compared to CON. IL-4 production induced by 0.5 and 1.0 MOI BHV-1 (D42 and D60); 0.25 MOI of BVDV type 1 (D21); and 0.25 and 0.5 MOI of BVDV type 2 (D60) were significantly higher for TRT than CON. IL-17 production induced by 0.25 MOI of BVDV type 1 was significantly higher on D60 for TRT compared to CON. IFN-gamma and IL-10 were not significantly different between treatments. These data indicate feeding OG has a beneficial effect on responses to vaccine antigens in Holstein dairy heifers.

Respiratory function in cattle: impact of breed, heritability and external factors.

Bovine respiratory disease complex (BRDC) is the most common and costly disease of cattle. The important prevalence of this multifactorial syndrome results from interactions between different pathogens, physical constitution of the host and environmental factors. Because of the strong economical impact of BRDC, it is recommended to complete classical preventive and therapeutic measures by selection of heritable traits improving resistance against respiratory disease and by alternatives based on improved control of environmental factors. The transport of oxygen between the atmospheric air and the mitochondria essentially includes four steps, i.e. (1) respiratory function, including pulmonary ventilation, perfusion and respiratory mechanics, (2) blood circulation and oxygen transport, (3) capillary-cell diffusion and (4) oxygen combustion by mitochondria. Each step should be considered when factors improving resistance against respiratory disease are investigated. This review aims (1) to summarise briefly the anatomical, histological and physiological peculiarities of the bovine respiratory system and (2) to consider the effect of breed, heritability and external factors at each step of the oxygen transport chain, by focussing essentially on respiratory function.

Potentiation of the humoral immune response elicited by a commercial vaccine against bovine respiratory disease by Enterococcus faecalis CECT7121.

Vaccination against pathogens involved in bovine respiratory disease (BRD) is a useful tool to reduce the risk of this disease however, it has been observed that the commercially available vaccines only partially prevent the infections caused by Pasteurella multocida and Mannheimia haemolytica. Therefore, it is recommended to search for new adjuvant strategies to minimise the economic impact of this respiratory syndrome. A possibility to improve the conventional vaccine response is to modulate the immune system with probiotics, since there is accumulating evidence that certain immunomodulatory strains administered around the time of vaccination can potentiate the immune response. Considering veterinary vaccines are frequently tested in murine models, we have developed an immunisation schedule in BALB/c mice that allows us to study the immune response elicited by BRD vaccine. In order to evaluate a potential strategy to enhance vaccine efficacy, the adjuvant effect of Enterococcus faecalis CECT7121 on the murine specific humoral immune response elicited by a commercial vaccine against BRD was studied. Results indicate that the intragastric administration of E. faecalis CECT7121 was able to induce an increase in the specific antibody titres against the bacterial components of the BRD vaccines (P. multocida and M. haemolytica). The quality of the humoral immune response, in terms of antibody avidity, was also improved. Regarding the cellular immune response, although the BRD vaccination induced a low specific secretion of cytokines in the spleen cell culture supernatants, E. faecalis CECT7121-treated mice showed higher interferon-γ production than immunised control mice. Our results allowed us to conclude that the administration of E. faecalis CECT7121 could be employed as an adjuvant strategy to potentiate humoral immune responses.

Comparative approaches to the investigation of responses to stress and viral infection in cattle.

Fatal bovine respiratory disease (BRD) is a major cause of financial losses in the cattle industry. A variety of stressors have been implicated as contributing to disease severity. However, it has proven difficult to determine the role these individual factors may play in the final outcome of this disease complex. The objective of the present investigation was to obtain proteomic, metabonomic, and elemental profiles of bovine serum samples from stressed and control animals before and after a primary viral infection to determine if these profiles could distinguish between responses to stressors and viral infection. Multivariate analysis revealed distinct differential trends in the distribution profile of proteins, metabolites, and elements following a stress response both before and after primary viral infection. A group of acute phase proteins, metabolites, and elements could be specifically linked to either a stress response (decreased serum amyloid A and Cu, increased apolipoprotein CIII, amino acids, LDL, P, and Mo) or a primary viral respiratory infection (increased apolipoprotein A1, haptoglobin, glucose, amino acids, LDL and Cu, decreased Lipid, and P). Thus, combined OMICS analysis of serum samples revealed that multimethod analysis could be used to discriminate between the complex biological responses to stress and viral infection.

A review of the biology of bovine herpesvirus type 1 (BHV-1), its role as a cofactor in the bovine respiratory disease complex and development of improved vaccines.

Infection of cattle by bovine herpesvirus type 1 (BHV-1) can lead to upper respiratory tract disorders, conjunctivitis, genital disorders and immune suppression. BHV-1-induced immune suppression initiates bovine respiratory disease complex (BRDC), which costs the US cattle industry approximately 3 billion dollars annually. BHV-1 encodes at least three proteins that can inhibit specific arms of the immune system: (i) bICP0 inhibits interferon-dependent transcription, (ii) the UL41.5 protein inhibits CD8+ T-cell recognition of infected cells by preventing trafficking of viral peptides to the surface of the cells and (iii) glycoprotein G is a chemokine-binding protein that prevents homing of lymphocytes to sights of infection. Following acute infection of calves, BHV-1 can also infect and induce high levels of apoptosis of CD4+ T-cells. Consequently, the ability of BHV-1 to impair the immune response can lead to BRDC. Following acute infection, BHV-1 establishes latency in sensory neurons of trigeminal ganglia (TG) and germinal centers of pharyngeal tonsil. Periodically BHV-1 reactivates from latency, virus is shed, and consequently virus transmission occurs. Two viral genes, the latency related gene and ORF-E are abundantly expressed during latency, suggesting that they regulate the latency-reactivation cycle. The ability of BHV-1 to enter permissive cells, infect sensory neurons and promote virus spread from sensory neurons to mucosal surfaces following reactivation from latency is also regulated by several viral glycoproteins. The focus of this review is to summarize the biology of BHV-1 and how this relates to BRDC.

Immune evasion by pathogens of bovine respiratory disease complex.

Bovine respiratory tract disease is a multi-factorial disease complex involving several viruses and bacteria. Viruses that play prominent roles in causing the bovine respiratory disease complex include bovine herpesvirus-1, bovine respiratory syncytial virus, bovine viral diarrhea virus and parinfluenza-3 virus. Bacteria that play prominent roles in this disease complex are Mannheimia haemolytica and Mycoplasma bovis. Other bacteria that infect the bovine respiratory tract of cattle are Histophilus (Haemophilus) somni and Pasteurella multocida. Frequently, severe respiratory tract disease in cattle is associated with concurrent infections of these pathogens. Like other pathogens, the viral and bacterial pathogens of this disease complex have co-evolved with their hosts over millions of years. As much as the hosts have diversified and fine-tuned the components of their immune system, the pathogens have also evolved diverse and sophisticated strategies to evade the host immune responses. These pathogens have developed intricate mechanisms to thwart both the innate and adaptive arms of the immune responses of their hosts. This review presents an overview of the strategies by which the pathogens suppress host immune responses, as well as the strategies by which the pathogens modify themselves or their locations in the host to evade host immune responses. These immune evasion strategies likely contribute to the failure of currently-available vaccines to provide complete protection to cattle against these pathogens.