Ruminant Diseases and Immunology Research Unit

Ames, IA, United States

Ruminant Diseases and Immunology Research Unit

Ames, IA, United States
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McGill J.L.,Kansas State University | Sacco R.E.,Ruminant Diseases and Immunology Research Unit
Veterinary Immunology and Immunopathology | Year: 2016

γδ T cells are a subset of nonconventional T cells that play a critical role in bridging the innate and adaptive arms of the immune system. γδ T cells are particularly abundant in ruminant species and may constitute up to 60% of the circulating lymphocyte pool in young cattle. The frequency of circulating γδ T cells is highest in neonatal calves and declines as the animal ages, suggesting these cells may be particularly important in the immune system of the very young. Bovine respiratory syncytial virus (BRSV) is a significant cause of respiratory infection in calves, and is most severe in animals under one year of age. BRSV is also a significant factor in the development of bovine respiratory disease complex (BRDC), the leading cause of morbidity and mortality in feedlot cattle. Human respiratory syncytial virus (RSV) is closely related to BRSV and a leading cause of lower respiratory tract infection in infants and children worldwide. BRSV infection in calves shares striking similarities with RSV infection in human infants. To date, there have been few studies defining the role of γδ T cells in the immune response to BRSV or RSV infection in animals or humans, respectively. However, emerging evidence suggests that γδ T cells may play a critical role in the early recognition of infection and in shaping the development of the adaptive immune response through inflammatory chemokine and cytokine production. Further, while it is clear that γδ T cells accumulate in the lungs during BRSV and RSV infection, their role in protection vs. immunopathology remains unclear. This review will summarize what is currently known about the role of γδ T cells in the immune response to BRSV and BRDC in cattle, and where appropriate, draw parallels to the role of γδ T cells in the human response to RSV infection. © 2016 Elsevier B.V.

Taxis T.M.,Ruminant Diseases and Immunology Research Unit | Bauermann F.V.,Ruminant Diseases and Immunology Research Unit | Ridpath J.F.,Ruminant Diseases and Immunology Research Unit | Casas E.,Ruminant Diseases and Immunology Research Unit
Frontiers in Genetics | Year: 2017

Bovine viral diarrhea virus (BVDV) is an RNA virus that is often associated with respiratory disease in cattle. MicroRNAs have been proposed as indicators of exposure to respiratory pathogens. The objective of this study was to identify microRNAs in cattle that had been challenged with a non-cytopathic field strain of BVDV. Five colostrum deprived neonate Holstein calves were inoculated with BVDV (challenged) and 4 were mock challenged (control). Serum from all calves was collected at four different times: prior to challenge (day 0) and at 4, 9, and 16 days post-challenge. RNA was extracted from sera, and expression, via read counts, of small non-coding RNAs were obtained using next-generation sequencing. A total of 905,861 sequences identified 427 microRNAs. Sixty-two microRNAs had <1,000 total reads across all samples. Bta-miR-339a, bta-miR-185, bta-miR-486, Bta-miR-92a, bta-miR-30e-5p, bta-let-7c, and bta-miR-2284x were significantly different (P > 0.05) across time regardless of challenge status. Bta-miR-423-5p (P = 0.008) and bta-miR-151-3p (P = 0.005) were significantly different between challenged and control animals across time. In challenged animals, bta-miR-423-5p peaked in number of reads by day 4 and steadily declined from day 4 to day 16. In control animals, bta-miR-423-5p declined from day 0 to day 9 and increased in number by day 16. By day 16, both challenged and control animals had similar levels of bta-miR-423-5p, and these levels were similar to day 0 levels. Bta-miR-151-3p peaked at day 9 in challenged animals, while control animals decreased across time. By day 16, the number of reads of bta-miR-151-3p were similar between challenged and control animals. The level in challenged animals had returned to day 0 levels by day 16, whereas the levels for control animals was significantly lower (P = 0.006) than day 0. Further studies are needed to establish if bta-miR-423-5p or bta-miR-151-3p could be used as a biomarker for exposure to BVDV. © 2017 Taxis, Bauermann, Ridpath and Casas.

Yilmaz H.,Istanbul University | Altan E.,Istanbul University | Ridpath J.,Ruminant Diseases and Immunology Research Unit | Turan N.,Istanbul University
Comparative Immunology, Microbiology and Infectious Diseases | Year: 2012

The aim of this study was to investigate the frequency and diversity of bovine viral diarrhea viruses (BVDV) infecting cattle in Turkey. A total of 1124 bovine blood samples from 19 farms in 4 different Turkish regions were tested by antigen capture ELISA (ACE). BVDV antigen was found in 26 samples from 13 farms. Only 20 of the 26 initial test positive cattle were available for retesting. Of these, 6 of 20 tested positive for BVDV, by ACE and real-time RT-PCR, one month after initial testing. Phylogenetic analysis, based on comparison of the E2 or the 5'UTR coding regions, from 19 of the 26 initial positive samples, indicated that 17 belonged to the BVDV-1 genotype and 2 to the BVDV-2 genotype. Comparison of 5'UTR sequences segregated 8 BVDV-1 strains (strains 5, 6, 10, 11, 12, 13, 17, and 19) to the BVDV1f, 1 strain (strain 8) to the BVDV1i and 1 strain (strain 14) to the BVDV1d subgenotypes. One strain (strain 4) did not group with other subgenotypes but was closer to the BVDV1f. The remaining 6 BVDV-1 strains (strains 1, 2, 3, 7, 9, and 18) segregated to a novel subgenotype. The E2 sequence comparison results were similar, with the exception that strain 5 grouped with the novel subgenotype rather than BVDV1f subgenotype. It appears that among the diverse BVDV strains in circulation there may be a subgenotype that is unique to Turkey. This should be considered in the design of diagnostics and vaccines to be used in Turkey. © 2012 Elsevier Ltd.

Ridpath J.F.,Ruminant Diseases and Immunology Research Unit
Animal Health Research Reviews | Year: 2015

Until the early 1990s there were just three recognized species in the pestivirus genus, bovine viral diarrhea virus (BVDV), border disease virus (BDV) and classical swine fever virus (CSFV). Subsequently BVDV were divided into two different species, BVDV1 and BVDV2 and four additional putative pestivirus species have been identified, based on phylogenetic analysis. The four putative pestivirus specices, listed in chronological order of published reports, are Giraffe (isolated from one of several giraffes in the Nanyuki District of Kenya suffering from mucosal disease-like symptoms), HoBi (first isolated from fetal bovine serum originating in Brazil and later from samples originating in Southeast Asia), Pronghorn (isolated from an emaciated blind pronghorn antelope in the USA), and Bungowannah (isolated following an outbreak in pigs, resulting in still birth and neonatal death, in Australia). In addition to the emergence of putative new species of pestivirus, changes in host and virulence of recognized or 'classic' pestiviruses have led to reevaluation of disease control programs and management of domestic and wildlife populations. © Cambridge University Press 2015.

Nelson C.D.,University of Wisconsin - Madison | Reinhardt T.A.,Ruminant Diseases and Immunology Research Unit | Lippolis J.D.,Ruminant Diseases and Immunology Research Unit | Sacco R.E.,Ruminant Diseases and Immunology Research Unit | Nonnecke B.J.,Ruminant Diseases and Immunology Research Unit
Nutrients | Year: 2012

The endocrine physiology of vitamin D in cattle has been rigorously investigated and has yielded information on vitamin D requirements, endocrine function in health and disease, general metabolism, and maintenance of calcium homeostasis in cattle. These results are relevant to human vitamin D endocrinology. The current debate regarding vitamin D requirements is centered on the requirements for proper intracrine and paracrine vitamin D signaling. Studies in adult and young cattle can provide valuable insight for understanding vitamin D requirements as they relate to innate and adaptive immune responses during infectious disease. In cattle, toll-like receptor recognition activates intracrine and paracrine vitamin D signaling mechanism in the immune system that regulates innate and adaptive immune responses in the presence of adequate 25-hydroxyvitamin D. Furthermore, experiments with mastitis in dairy cattle have provided in vivo evidence for the intracrine vitamin D signaling mechanism in macrophages as well as vitamin D mediated suppression of infection. Epidemiological evidence indicates that circulating concentrations above 32 ng/mL of 25-hydroxyvitamin D are necessary for optimal vitamin D signaling in the immune system, but experimental evidence is lacking for that value. Experiments in cattle can provide that evidence as circulating 25-hydroxyvitamin D concentrations can be experimentally manipulated within ranges that are normal for humans and cattle. Additionally, young and adult cattle can be experimentally infected with bacteria and viruses associated with significant diseases in both cattle and humans. Utilizing the bovine model to further delineate the immunomodulatory role of vitamin D will provide potentially valuable insights into the vitamin D requirements of both humans and cattle, especially as they relate to immune response capacity and infectious disease resistance. © 2012 by the authors; licensee MDPI, Basel, Switzerland.

Mcgill J.L.,Ruminant Diseases and Immunology Research Unit | Nonnecke B.J.,Ruminant Diseases and Immunology Research Unit | Lippolis J.D.,Ruminant Diseases and Immunology Research Unit | Reinhardt T.A.,Ruminant Diseases and Immunology Research Unit | Sacco R.E.,Ruminant Diseases and Immunology Research Unit
Immunology | Year: 2013

γδ T cells respond to stimulation via toll-like receptors (TLR). Bovine γδ T cells express TLR3 and TLR7, receptors that are key for the recognition of viruses such as bovine respiratory syncytial virus (BRSV); however, responses of γδ T cells to stimulation via these receptors, and their role during viral infections, remains unclear. Here, we demonstrate that neonatal bovine γδ T cells exhibit robust chemokine and cytokine production in response to the TLR3 agonist, Poly(I:C), and the TLR7 agonist, Imiquimod. Importantly, we observe a similar phenotype in γδ T-cell subsets purified from calves infected with BRSV. Bovine γδ T cells are divided into subsets based upon their expression of WC1, and the response to TLR stimulation and viral infection differs between these subsets, with WC1.1+ and WC1neg γδ T cells producing macrophage inflammatory protein-1α and granulocyte-macrophage colony-stimulating factor, and WC1.2+ γδ T cells preferentially producing the regulatory cytokines interleukin-10 and transforming growth factor-β. We further report that the active vitamin D metabolite 1,25-dihydroxyvitamin D3 does not alter γδ T-cell responses to TLR agonists or BRSV. To our knowledge, this is the first characterization of the γδ T-cell response during in vivo BRSV infection and the first suggestion that WC1.1+ and WC1neg γδ T cells contribute to the recruitment of inflammatory populations during viral infection. Based on our results, we propose that circulating γδ T cells are poised to rapidly respond to viral infection and suggest an important role for γδ T cells in the innate immune response of the bovine neonate. © 2013 Blackwell Publishing Ltd.

Waters W.R.,Infectious Bacterial Diseases of Livestock Research Unit | Maggioli M.F.,Infectious Bacterial Diseases of Livestock Research Unit | McGill J.L.,Ruminant Diseases and Immunology Research Unit | Lyashchenko K.P.,Chembio Diagnostic Systems, Inc. | Palmer M.V.,Infectious Bacterial Diseases of Livestock Research Unit
Veterinary Immunology and Immunopathology | Year: 2014

Pioneer studies on infectious disease and immunology by Jenner, Pasteur, Koch, Von Behring, Nocard, Roux, and Ehrlich forged a path for the dual-purpose with dual benefit approach, demonstrating a profound relevance of veterinary studies for biomedical applications. Tuberculosis (TB), primarily due to Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle, is an exemplary model for the demonstration of this concept. Early studies with cattle were instrumental in the development of the use of Koch's tuberculin as an in vivo measure of cell-mediated immunity for diagnostic purposes. Calmette and Guerin demonstrated the efficacy of an attenuated M. bovis strain (BCG) in cattle prior to use of this vaccine in humans. The interferon-γ release assay, now widely used for TB diagnosis in humans, was developed circa 1990 for use in the Australian bovine TB eradication program. More recently, M. bovis infection and vaccine efficacy studies with cattle have demonstrated a correlation of vaccine-elicited T cell central memory (TCM) responses to vaccine efficacy, correlation of specific antibody to mycobacterial burden and lesion severity, and detection of antigen-specific IL-17 responses to vaccination and infection. Additionally, positive prognostic indicators of bovine TB vaccine efficacy (i.e., responses measured after infection) include: reduced antigen-specific IFN-γ, iNOS, IL-4, and MIP1-α responses; reduced antigen-specific expansion of CD4+ T cells; and a diminished activation profile on T cells within antigen stimulated cultures. Delayed type hypersensitivity and IFN-γ responses correlate with infection but do not necessarily correlate with lesion severity whereas antibody responses generally correlate with lesion severity. Recently, serologic tests have emerged for the detection of tuberculous animals, particularly elephants, captive cervids, and camelids. B cell aggregates are consistently detected within tuberculous lesions of humans, cattle, mice and various other species, suggesting a role for B cells in the immunopathogenesis of TB. Comparative immunology studies including partnerships of researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in both man and animals. © 2014.

Darweesh M.F.,Brookings Biomedical | Rajput M.K.S.,Brookings Biomedical | Braun L.J.,Brookings Biomedical | Ridpath J.F.,Ruminant Diseases and Immunology Research Unit | And 2 more authors.
Virus Research | Year: 2015

Bovine viral diarrhea virus (BVDV) is a positive single stranded RNA virus belonging to the Pestivirus genus of the Flaviviridae family. BVDV has a wide host range that includes most ruminants. Noncytopathic (ncp) BVDV may establish lifelong persistent infections in calves following infection of the fetus between 40 and 120 days of gestation. Cytopathic (cp) BVDV strains arise from ncp strains via mutations. The most common cp mutations are insertions of RNA derived from either host or a duplication of viral sequences into the region of the genome coding for the NS2/3 protein. Superinfection of a persistently infected animal with a cp virus can give rise to mucosal disease, a condition that is invariably fatal. A herd of 136 bred 3-year old cows was studied. These cows gave birth to 41 PI animals of which 23 succumbed to mucosal disease. In this study, we characterized the ncp and cp viruses isolated from 13 of these animals. All viruses belonged to the BVDV type 2a genotype and were highly similar. All the cp viruses contained an insertion in the NS2/3 coding region consisting of the sequences derived from the transcript encoding a DnaJ protein named Jiv90. Comparison of the inserted DnaJ regions along with the flanking viral sequences in the insertion 3' end of the 13 cp isolates revealed sequence identities ranging from 96% to 99% with common borders. This suggested that one animal likely developed a cp virus that then progressively spread to the other 12 animals. Interestingly, when the inserted mammalian gene replicated within viral genome, it showed conservation of the same conserved motifs between the different species, which may indicate a role for these motifs in the insertion function within the virus genome. This is the first characterization of multiple cp bovine viral diarrhea virus isolates that spread in a herd under natural conditions. © 2014 Elsevier B.V.

Sacco R.E.,Ruminant Diseases and Immunology Research Unit | Nonnecke B.J.,Ruminant Diseases and Immunology Research Unit | Palmer M.V.,Infectious Bacterial Diseases Research Unit | Waters W.R.,Infectious Bacterial Diseases Research Unit | And 2 more authors.
PLoS ONE | Year: 2012

Deficiency of serum levels of 25-hydroxyvitamin D 3 has been related to increased risk of lower respiratory tract infections in children. Respiratory syncytial virus (RSV) is a leading cause of low respiratory tract infections in infants and young children. The neonatal calf model of RSV infection shares many features in common with RSV infection in infants and children. In the present study, we hypothesized that calves with low circulating levels of 25-hydroxyvitamin D 3 (25(OH)D 3) would be more susceptible to RSV infection than calves with high circulating levels of 25(OH)D 3. Calves were fed milk replacer diets with different levels of vitamin D for a 10 wk period to establish two treatment groups, one with high (177 ng/ml) and one with low (32.5 ng/ml) circulating 25(OH)D 3. Animals were experimentally infected via aerosol challenge with RSV. Data on circulating 25(OH)D 3 levels showed that high and low concentrations of 25(OH)D 3 were maintained during infection. At necropsy, lung lesions due to RSV were similar in the two vitamin D treatment groups. We show for the first time that RSV infection activates the vitamin D intracrine pathway in the inflamed lung. Importantly, however, we observed that cytokines frequently inhibited by this pathway in vitro are, in fact, either significantly upregulated (IL-12p40) or unaffected (IFN-γ) in the lungs of RSV-infected calves with high circulating levels of 25(OH)D 3. Our data indicate that while vitamin D does have an immunomodulatory role during RSV infection, there was no significant impact on pathogenesis during the early phases of RSV infection. Further examination of the potential effects of vitamin D status on RSV disease resolution will require longer-term studies with immunologically sufficient and deficient vitamin D levels.

Ridpath J.,Ruminant Diseases and Immunology Research Unit
Veterinary Clinics of North America - Food Animal Practice | Year: 2010

The contribution of bovine viral diarrhea viruses (BVDV) to the development of bovine respiratory disease is the sum of several different factors. These factors include the contribution of acute uncomplicated BVDV infections, the high incidence of respiratory disease in animals persistently infected with BVDV, the immunosuppression that accompanies acute BVDV infections and predisposes animals to secondary infections, and the synergy resulting in increased virulence occurring in coinfections of BVDV with other pathogens. Immunosuppression, which is associated with infection with all BVDV, may have the greatest impact of these factors. Control of BVDV infections rests on reducing exposure by removing BVDV persistently infected animals, increasing herd resistance by vaccination, and instituting biocontrol methods that limit the opportunity for introduction of BVDV into herds and management units. © 2010.

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