William C. Davis
|Department:||Veterinary Microbiology & Pathology, WSU|
|Credentials:||1967 - Ph.D., Stanford University - Medical Microbiology, Transplantation Immunology|
|Mailing Address:||Veterinary Microbiology &Pathology|
PO Box 647040
Pullman, WA 99164-7040
|Web Site:||Click here|
The study of mechanisms regulating the immune response to infectious agents and vaccines.
The long term objectives of our research program are to elucidate the mechanisms regulating the immune response to infectious agents and develop protective vaccines. To achieve these objectives, we continue to develop and use monoclonal antibodies and assays to study the immune response in domestic animals with a primary focus on ruminants. M. avium subsp. Paratuberculosis (Map) has been selected as the model pathogen for our investigations because of its economic importance and its potential for providing insight into the mechanisms regulating the immune response to Map and other intracellular pathogens. Map is the causative agent of Johne’s disease (JD) in cattle, a chronic wasting disease of the intestine. It causes significant economic loss to producers, especially the dairy industry, due to increase in forage consumption, decreased milk production and early culling due to poor health of affected animals. There is also a concern that Map is a zoonotic pathogen. Map has been isolated from human patients with Crohn’s disease (CD), a chronic inflammatory disease of the intestine. It is not clear whether Map is the etiologic agent causing Crohn’s disease. However, recent studies on CD and mycobacterial pathogens M. tuberculosis (Mtb) and Map have shown a similarity in the mechanisms of pathogenesis at the cellular and molecular level. The studies have revealed the cross regulation of the immune system by regulatory T cells and effector T cells mediating protective immune responses is dysregulated, giving rise to an imbalance that results in chronic inflammation of target tissues, and in the case of Mtb and Map dysregulation of protective immunity. To extend these observation we developed a bovine cannulated ileum model to conduct studies on the mechanisms of pathogenesis mediated by Map in the natural host, studies that cannot be conducted in humans. The model offers an opportunity to study the interaction of Map during the early and late stages of infection. We have also developed a flow cytometric assay to analyze the immune response to Map and methods to elucidate the functional changes associated with dysregulation of the immune system. More recently, we developed deletion mutants of Map. One of the mutations abrogates the capacity of Map to establish a persistent infection. This is an exceptional breakthrough providing opportunities to identify the pathways used by Map to evade immune elimination and establish a persistent infection. The findings should allow us to identify the bacterial antigens that modulate the immune response for use in vaccine development. We also believe the studies will show Map could be involved in the pathogenesis of CD.
The working hypothesis is:
Antigen presenting dendritic cells (DC) play a central role in the development and maintenance of protective immunity against Map and that dysregulation of DC function allows for disease progression.
The specific objectives to test the hypothesis are:
- Determine how Map affects DC maturation and secretion of regulatory cytokines and chemokines in vitro.
- Detail the primary CD4 and CD8 T cell immune responses mediated by immature DC (iDC) and matured DC (mDC) following exposure to different antigenic stimuli in vitro.
- Determine if regulatory DC (DCr) and regulatory T cells (Tf) play a role in modulating the immune response to Map.
Park KT, Allen AJ, Davis WC. Development of a novel DNA extraction method for identification and quantification of Mycobacterium avium sbsp. Paratuberculosis from tissue samples by real-time PCR. J. Microbiological Methods 99:58, 2014.
Park KT, Davis WC. Therapeutic Potential of a Candidate relA Deletion Mutant Vaccine of Mycobacterium avium subspecies paratuberculosis. Advances An Vet Sci 2-26-14
Faisal SM, Chen JW, Yan F, Chen TT, Useh NM, Yan W, Guo S, Wang SJ, Glaser AL, McDonough SP, Singh B, Davis WC, Akey BL, Chang YF. Evaluation of Mycobacterium avium sunsp. Paratuberculosis leuD mutantas vaccine candidate against challenge in a caprine model. Clin. Vaccine Immunol. 20:572-582, 2013.
Lund H, Boysen P, Dean GA, Davis WC, Park KT, STorset AK. Interleukin-15 activated bovine natural killer cells express CD69 and produce interferon-γ. Vet. Immunol. Immunopathol. 150:79-89. 2012.
Shuraley E, Quinn P, Doyle M, Duignan A, Kwok HF, Bezos J, Owill SA, Gomley E, Aranaz A, Good M, Davis WC, Clarke J, Whelan C. Application of the Enfer chemiluminescent multiplex ELISA system for the detection of Mycobacterium bovis infection in goats. Vet. Microbiol. 154:292-297. 2012.
Davis WC, Madsen-Bouterse SA. Crohn’s disease and Mycobacterium avium subsp. Aratuberculosis, the need for a study is long overdue. Vet. Immunol. Immunopathol. 154:1-6, 2012.
Njongmeta LM, Bray J, Davies CJ, Davis WC, Howard CJ, Hope JC, Paler GH, Brown WC, Mwangi W. CD205 antigen targeting combined with dendritic cell recruitment factors and antigen-linked CD40L activation primes and expands significant antigen-specific antibody and CD4(+) T cell responses following dNA vaccination of outbred animals. Vaccine 30:1624-1635. 2012.
Dassanayake RP, Schneider DA, Hermann-Hoesing LM, Truscott TC, Davis WC, O’Kourke KI.Cell-surface expression of PrPc and the presence of scrapie prions in the blood of goats. J. Gen. Virol. 93:1127-1131. 2012.
Lamont E, O’Grady S, Davis W, Eckstein T, Sreevatsan S. Infection with Mycobacterium avius subsp. paratuberculosis results in rapid IL-1β release and macrophage transepithelial migration. Infect. Immun. 80:3225-323. 2012.
Wu LY, Lie T, Hopkins MR, Davis WC, Berkman CE. Chemoaffinity capture of pre-targeted prostate cancer cells with magnetic beads. Prostate. 72:1532-154. 2012.
Cunha CW, Gailbreath KL, O’Toole D, Knowles DP, Schneider DA, White SN, Taus NS, Davis WC, Li H. Ovine herpes virus 2 infection in American bison: virus and host dynamics in the development of sheep-associated malignant catarrgal fever. Vet. Microbiol. 159:307-319. 2012.
Allen AJ, Stabel JR, Robbe-Austerman S, Park KT, Palmer MV, Barrington GM, Lahmers KK, Hamilton MJ, Davis WC. Depletion of CD4 T lymphocytes at the time of infection with M. avium subsp. Paratuberculosis does not accelerate disease progression. Vet. Immunol. Immunopathol. 149:2896-291. 2012.
Lund H, Boysen P, Dean GA, Davis WC, Park KT, Storset AK. Interleukin-15 activated bovine natural killer cells express CD69 and produce interferon-γ. Vet. Immunol. Immunopathol. 150:79-89. 2012.
Allen AJ, Park KT, Barrington GM, Lahmers KL, Abdellrazeq GS, Rihan HM, Sreevatsan S, Davies C, Hamilton MJ, Davis WC. (2011) Experimental infection of a bovine model with human isolates of Mycobacterium avium subsp. paratuberculosis. Vet. Immunol. Immunopathol. 141:258-266.
Whelan C, Shuralev E, Kwok HF, Kenny K, Duignan A, Good M, Davis WC, Clarke J. (2011) Use of a multiplex enzyme-linked immunosorbent assay to detect a sub-population of Mycobacterium bovis-infected animals deemed negative or inconclusive by the single intradermal comparative tuberculin test. J. Vet. Diagn. Invest. 23:499-503.
Park Kt, Allen AJ, Bannantine JP, Seo KS, Hamilton MJ, Abdellrazeq GS, Rihan HM, Grimm A, Davis WC. (2011) Evaluation of two mutants of Mycobacterium avium subsp. paratuberculosis as candidates for a live attenuated vaccine for Johne’s disease. Vaccine 29:4709-4719.
Waters WR, Palmer MV, Thacker TC, Davis WC, Sreevatsan SS, Coussens P, Meade KG, Hope J, Estes DM. (2011) Tuberculosis immunity: Opportunities from studies with cattle. Clin. Dev. Immunol. 2011:Article ID-768542, 11 pages.
Nelson DD, WC Davis, et al. (2010). “CD8(+)/perforin(+)/WC1(-) gammadelta T cells, not CD8(+) alphabeta T cells, infiltrate vasculitis lesions of American bison (Bison bison) with experimental sheep-associated malignant catarrhal fever.” Veterinary Immunology and Immunopathology 136(3-4): 284-291.
Seo KS, Davis WC, Hamilton MJ, Park YH, Bohach GA. Development of monoclonal antibodies to detect bovine FOXP3 in PBMCs exposed to a staphylococcal superantigen. Vet Immunol. Immunopathol 128:30-36, 2009.
Seo KS, Park JY, Davis WC, Fox LK, McGuire MA, Park YH, Bohach GA. Superantigen-mediated differentiation of bovine monocytes unto dendritic cells. J. Leukoc. Biol. 85:606-616, 2009.
Allen AJ, Park KT, Barrington GM, Lahmers KK, Hamilton MJ and WC Davis. "Development of a bovine ileal cannulation model to study the immune response and mechanisms of pathogenesis of paratuberculosis." Clin. Vaccine. Immunol, 2009. 16(4)(:p. 453-63.
Detzel CJ, Mason DJ, Davis WC, van Wie BJ. Kinetic simulation of a centrifugal bioreactor for high population density hybridoma culture. Biotechnol. Prog. 6:1650-1659, 2009.
Davis WC, Park KT, Hamilton MJ, Waters WR. Understanding the mechanisms of immunopathogenesis of human and bovine tuberculosis. J Zoonoses 1:17-23, 2010.
Dassanayake RP, W Liu, WC Davis, WJ Foreyt and S. Srikumaran. "Bighorn sheep beta2-integrin LFA-1 serves as a receptor for Mannheimia haemolytica leukotoxin." J. Wildl. Dis, 2008. 44(3):p.743-7.
Whelan C, Shuralev E, O’Keefe G, Hyland P, Kwok HF, Snoddy P, O’Brien A, Connolly M, Quinn P, Groll M, Watterson T, Call S, Kenny K, Duignan A, Hamilton MJ, Buddle BM, Johnston JA, Davis WC, Olwill S, Clarke J. Multiplex immunoassay for the serological diagnosis of Mycobacterium bovis infected cattle. Clin. Vaccine Immunol. 15:1834-1838, 2008.
Davis WC and MJ Hamilton. "Use of flow cytometry to develop and characterize a set of monoclonal antibodies specific for rabbit leukocyte differentiation molecules." J. Vet. Sci., 2008. 9(1): p. 51-66.
Johnson, WC, RG Bastos, WC Davis, and WL Goff. "Bovine WC1(-) gammadeltaT cells incubated with IL-15 express the natural cytotoxicity receptor CD335 (NKp46) and produce IFN-gamma in response to exogenous IL-12 and IL-18." Dev Comp Immunol, 2008. 32(8): p. 1002-10.
Mealey, RH, MH Littke, SR Leib, WC Davis, and TC McGuire. "Failure of low-dose recombinant human IL-2 to support the survival of virus-specific CTL clones infused into severe combined immunodeficient foals: lack of correlation between in vitro activity and in vivo efficacy." Vet Immunol Immunopathol, 2008. 121(1-2): p. 8-22.
Park, KT, JL Dahl, JP Bannantine, RG Barletta, J Ahn, AJ Allen, MJ Hamilton, and WC Davis. "Demonstration of allelic exchange in the slow-growing bacterium Mycobacterium avium subsp. paratuberculosis, and generation of mutants with deletions at the pknG, relA, and lsr2 loci." Appl Environ Microbiol, 2008. 74(6): p. 1687-95.