Bacterial pathogens must avoid clearance by the immune system to establish infection, yet many mechanisms of bacterial immune subversion remain undefined. A number of bacterial pathogens subvert pathways of the innate immune system, but how bacterial pathogens overcome pathways of the adaptive immune system is not well understood. T cells are a key component of the adaptive immune system and are required for protective immunity against many bacterial pathogens. Salmonella enterica serovar Typhimurium (S. typhimurium) are pathogenic bacteria that inhibit the response of T cells directly, but the factor responsible for this inhibition has not been identified. We recently showe that S. typhimurium inhibit T cell responses by producing L- asparaginase II, which hydrolyzes L-asparagine. L-asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production and proliferation, and to down-modulate expression of the T cell receptor. Furthermore, S. typhimurium-induced inhibition of T cells in vitro is prevented upon addition of exogenous L-asparagine. S. typhimurium lacking the L-asparaginase II gene are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-asparaginases are used clinically to treat acute lymphoblastic leukemia, yet production of L-asparaginase II by pathogenic bacteria has been unrecognized as a mechanism of microbial immune subversion. The research proposed in this application will 1) determine the mechanism by which L-asparaginase II produced by S. typhimurium inhibits T cell responses and mediates virulence, and 2) determine the role of L-asparaginase II in the pathogenesis of, and host response to, infection with S. typhimurium. Completion of the proposed research will provide answers to important mechanistic questions and will provide a vastly enhanced perspective on the role of T cells in protective immunity against S. typhimurium. Given that the L-asparaginase II gene is highly conserved in Gram-negative bacteria and has been shown to contribute to virulence of several important human pathogens, our findings may extend well beyond S. typhimurium. Insights from the proposed research will have fundamental implications for understanding host interactions with bacterial pathogens and could lead to the development of new broad- spectrum therapeutic approaches and preventive measures to overcome bacterial infectious diseases.
Microbial pathogens that infect humans have evolved the ability to co-opt or subvert the immune response as a strategy to promote disease. This application will investigate a previously unrecognized mechanism of bacterial immune subversion. The proposed research will have significant fundamental implications for understanding host interactions with bacterial pathogens and thus contribute to improving human health.
|McLaughlin, Patrick A; McClelland, Michael; Yang, Hee-Jeong et al. (2017) Contribution of Asparagine Catabolism to Salmonella Virulence. Infect Immun 85:|
|McLaughlin, Patrick A; van der Velden, Adrianus W M (2016) Salmonella Gives MARCH(ing) Orders to MHC-II. Cell Host Microbe 20:551-552|
|Torres, AnnMarie; Luke, Joanna D; Kullas, Amy L et al. (2016) Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming. J Leukoc Biol 99:387-98|
|Zhang, Yue; Tam, Jason W; Mena, Patricio et al. (2015) CCR2+ Inflammatory Dendritic Cells and Translocation of Antigen by Type III Secretion Are Required for the Exceptionally Large CD8+ T Cell Response to the Protective YopE69-77 Epitope during Yersinia Infection. PLoS Pathog 11:e1005167|
|Cieniewicz, Brandon; Dong, Qiwen; Li, Gang et al. (2015) Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1? Production upon Extrinsic Stimulation in Culture. J Virol 89:6562-74|
|DelGiorno, Kathleen E; Tam, Jason W; Hall, Jason C et al. (2014) Persistent salmonellosis causes pancreatitis in a murine model of infection. PLoS One 9:e92807|
|Tam, Jason W; Kullas, Amy L; Mena, Patricio et al. (2014) CD11b+ Ly6Chi Ly6G- immature myeloid cells recruited in response to Salmonella enterica serovar Typhimurium infection exhibit protective and immunosuppressive properties. Infect Immun 82:2606-14|
|Kullas, Amy L; McClelland, Michael; Yang, Hee-Jeong et al. (2012) L-asparaginase II produced by Salmonella typhimurium inhibits T cell responses and mediates virulence. Cell Host Microbe 12:791-8|