Analysis of Listeria monycytogenes virulence and modulation of host IFNgamma responses

Listeria monocytogenes is an intracellular Gram-positive bacterium. Infection induces a robust innate immune response and requires T cells and the adaptive immune response for bacterial clearance. Many bacterial proteins contribute to L. monocytogenes virulence, including the autolysin p60. Autolysins play a role in degradation of the bacterial cell wall and may aid in the release of stimulatory peptidoglycan fragments into host cells during bacterial growth. The p60 autolysin is required for in vivo, but not in vitro bacterial expansion. Bacterial expression of p60 also enhances NK cell production of the inflammatory cytokine IFNgamma during the innate immune response. Generally, L. monocytogenes infection of dendritic cells induces multiple pro-inflammatory cytokines (IL-12, TNFalpha, IL-1beta, IL-18) that promote IFNgamma production by NK cells. Furthermore, cell contact between infected dendritic cells and responding NK cells is also required for efficient IFNgamma production during infection. One of the roles of IFNgamma is to activate macrophages to kill intracellular bacteria. While L. monocytogenes infection promotes IFNgamma production, it also utilizes cross-talk between the IFNAR and IFNGR to inhibit IFNgamma-dependent signaling. Type I IFN produced during L. monocytogenes infection down-regulates surface expression of the IFNGR. Inhibition of IFNGR signaling prevents activation of macrophages and other antigen-presenting cells, and thus reduces their ability to acquire bactericidal properties, such as up-regulation of MHC molecules, and production of reactive oxygen and nitrogen species. Lack of macrophage activation would allow for increased bacterial expansion, and likely contributes to L. monocytogenes virulence within the host.