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.
Research SummaryThe 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 has offered an opportunity to study the interaction of Map during the early and late stages of infection. We have also developed and used 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. Use of these methods in conjunction with development of methods to monitor the intracellular killing of bacteria by cytotoxic T cells have facilitated analysis of the functional activity of cytotoxic T cells responding to Map and derived candidate antigens. Ongoing studies with a mutant of Map, with a deletion in relA, has shown deletion abrogates the capacity of the mutant to establish a persistent infection. Further studies have shown the target of the immune response is directed towards a membrane protein (MMP). Ex vivo studies have shown stimulation with the MMP leads to the development of cytotoxic T cells with the capacity to kill intracellular bacteria. This major finding indicates a peptide based vaccine is possible against a major pathogen. These findings will now be used to advance our studies to the next phase, development and validation of a virus vector containing the gene encoding the MMP as a vaccine for JD.
Davis, W.C., Kuenstner, J.T., Singh, S.V., 2017. Resolution of Crohn's (Johne's) disease with antibiotics: what are the next steps? Expert Rev Gastroenterol Hepatol, 1-4.
Elnaggar, M.M., Abdellrazeq, G.S., Elsisy, A., Mahmoud, A.H., Shyboub, A., Sester, M., Khaliel, S.A., Singh, M., Torky, H.A., Davis, W.C., 2017. Evaluation of antigen specific interleukin-1beta as a biomarker to detect cattle infected with Mycobacterium bovis. Tuberculosis (Edinb) 105, 53-59.
Grandoni, F., Elnaggar, M.M., Abdellrazeq, G.S., Signorelli, F., Fry, L.M., Marchitelli, C., Hulubei, V., Khaliel, S.A., Torky, H.A., Davis, W.C., 2017. Characterization of leukocyte subsets in buffalo (Bubalus bubalis) with cross-reactive monoclonal antibodies specific for bovine MHC class I and class II molecules and leukocyte differentiation molecules. Dev Comp Immunol 74, 101-109.
Hussein, H.E., Bastos, R.G., Schneider, D.A., Johnson, W.C., Adham, F.K., Davis, W.C., Laughery, J.M., Herndon, D.R., Alzan, H.F., Ueti, M.W., Suarez, C.E., 2017. The Babesia bovis hap2 gene is not required for blood stage replication, but expressed upon in vitro sexual stage induction. PLoS Negl Trop Dis 11, e0005965.
McEntire, M.C., Wardrop, K.J., Davis, W.C., 2017. Comparison of established and novel methods for the detection and enumeration of microparticles in canine stored erythrocyte concentrates for transfusion. Vet Clin Pathol 46, 54-63.
Elnaggar, M.M., Abdellrazeq, G.S., Mack, V., Fry, L.M., Davis, W.C., and Park, K.T. (2016). Characterization and use of new monoclonal antibodies to CD11c, CD14, and CD163 to analyze the phenotypic complexity of ruminant monocyte subsets. Vet Immunol Immunopathol 178, 57-63.
Highland, M.A., Schneider, D.A., White, S.N., Madsen-Bouterse, S.A., Knowles, D.P., and Davis, W.C. (2016). Differences in leukocyte differentiation molecule abundances on domestic sheep (Ovis aries) and bighorn sheep (Ovis canadensis) neutrophils identified by flow cytometry. Comp Immunol Microbiol Infect Dis 46, 40-46.
Parasar, P., Wilhelm, A., Rutigliano, H.M., Thomas, A.J., Teng, L., Shi, B., Davis, W.C., Suarez, C.E., New, D.D., White, K.L., and Davies, C.J. (2016). Expression of bovine non-classical major histocompatibility complex class I proteins in mouse P815 and human K562 cells. Res Vet Sci 107, 161-170.
Abdellrazeq GS, Elnaggar MM, Osman HS, Davis WC, Singh M. 2016. Prevalence of Bovine Tuberculosis in Egyptian Cattle and the Standardization of the Interferon-gamma Assay as an Ancillary Test. Transbound Emerg Dis 63:497-507.
Park KT, ElNaggar MM, Abdellrazeq GS, Bannantine JP, Mack V, Fry LM, Davis WC. 2016. Phenotype and Function of CD209+ Bovine Blood Dendritic Cells, Monocyte-Derived-Dendritic Cells and Monocyte-Derived Macrophages. PLoS One 11:e0165247.
Tuo W, Li L, Lv Y, Carrillo J, Brown D, Davis WC, Song J, Zarlenga D, Xiao Z. 2016. Abomasal mucosal immune responses of cattle with limited or continuous exposure to pasture-borne gastrointestinal nematode parasite infection. Vet Parasitol 229:118-125.
Singh SV, Kuenstner JT, Davis WC, Agarwal P, Kumar N, Singh D, Gupta S, Chaubey KK, Kumar A, Misri J, Jayaraman S, Sohal JS, Dhama K. 2016. Concurrent Resolution of Chronic Diarrhea Likely Due to Crohn's Disease and Infection with Mycobacterium avium paratuberculosis. Front Med (Lausanne) 3:49.