Antibodies are thought to have limited protective efficacy against intracellular pathogens since they haverestricted access to intracellular compartments. However, growing evidence indicates that specific antibodiesplay a significant role in conferring sterilizing immunity by a close and critical association with cell-mediatedimmune responses. The specific mechanisms of the synergistic effect of cell-mediated and humoral responses,however, remain poorly understood. In the case of Francisella tularensis, antibodies together with the cytokineIFN- were shown to be critical in achieving rapid bacterial elimination in vivo. Furthermore, in vitro data suggest that a rapid intracellular killing of F. tularensis could be achieved if bacteria are opsonized with specificantibodies and are internalized by IFN- -activated phagocytes. These observations lead to the hypothesis thatrapid intracellular killing of intracellular bacteria by phagocytes requires the synergistic effect of IFN- -and Fc receptor-mediated cellular events. This proposal is designed to investigate the effect of IFN- onthe fate of bacteria internalized via Fc R by professional phagocytes and enhance the efficacy of antibodiesusing adjunct cytokines such as IFN- therapy with the following specific aims: I) to determine intracellular RNS and ROS dependent bactericidal mechanisms that lead to rapid killing of opsonized F. tularensis by IFN- -activated phagocytes, II) To determine the Fc R- and IFN- R-dependent signaling events leading to RNS andROS generation by IFN- -activated macrophages following internalization of opsonized F. tularensis, and III) toestablish the trafficking of opsonized F. tularensis to various intracellular compartments of IFN- -activatedphagocytes.The results obtained will advance our understanding of interactions between humoral and cell-mediatedimmune responses against intracellular pathogens. The potential applications of the outcome of the study mayinclude the design of novel prophylactic and therapeutic strategies not only against F. tularensis, but also otherintracellular bacteria such as M. tuberculosis and L. pneumophila. The proposed study will also facilitatetraining of PI in the areas of cell and molecular biology and its application in mucosal immunobiology, areas ofimmediate and long term career objectives, respectively, of the candidate. The proposal and researchenvironment at the mentor's lab complements the PI's desire to utilize basic understanding of cellularprocesses for therapeutic applications.
There are no vaccines available against Francisella tularensis and antibody-based therapies have limited efficacy against extremely virulent form of the bacteria, the form most likely to be used by bioterrorists. We have discovered that addition of cytokine with antibodies provide improved protection and the current proposal is designed to understand the mechanism fo synergy between antibodies and cytokines. These studies will result in the design of novel adjunct pharamacological agents to improve the antibody-based therapies against various bacterial pathogens.
| Williamson, David R; Dewan, Kalyan K; Patel, Tanmay et al. (2018) A Single Mechanosensitive Channel Protects Francisella tularensis subsp. holarctica from Hypoosmotic Shock and Promotes Survival in the Aquatic Environment. Appl Environ Microbiol 84: |
| Place, David E; Muse, Sarah J; Kirimanjeswara, Girish S et al. (2014) Caspase-1-independent interleukin-1? is required for clearance of Bordetella pertussis infections and whole-cell vaccine-mediated immunity. PLoS One 9:e107188 |
