IL-22 Signaling Contributes to West Nile Encephalitis Pathogenesis

The Th17 cytokine, IL-22, regulates host immune responses to extracellular pathogens. Whether IL-22 plays a role in viral infection, however, is poorly understood. We report here that Il22-/- mice were more resistant to lethal West Nile virus (WNV) encephalitis, but had similar viral loads in the periphery compared to wild type (WT) mice. Viral loads, leukocyte infiltrates, proinflammatory cytokines and apoptotic cells in the central nervous system (CNS) of Il22-/- mice were also strikingly reduced. Further examination showed that Cxcr2, a chemokine receptor that plays a non-redundant role in mediating neutrophil migration, was significantly reduced in Il22-/- compared to WT leukocytes. Expression of Cxcr2 ligands, cxcl1 and cxcl5, was lower in Il22-/- brains than wild type mice. Correspondingly, neutrophil migration from the blood into the brain was attenuated following lethal WNV infection of Il22-/- mice. Our results suggest that IL-22 signaling exacerbates lethal WNV encephalitis likely by promoting WNV neuroinvasion

Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22–dependent intestinal pathology

Interleukin-10 acts directly on CD45RBlo but not CD45RBhi cells to control colitis upon transfer into Rag1-deficient recipients

Modulation of the immune response by Gram -positive bacterial pathogens

Pathogens have evolved mechanisms to counteract different arms of the immune system. By downmodulating components of the immune response, a pathogen can interfere with the ability of the immune system to respond appropriately to each infection. In these studies, we examine how two different Gram-positive pathogens, Listeria monocytogenes and Bacillus anthracis, modulate the immune response. L. monocytogenes is a facultative intracellular pathogen that is an ideal pathogen for modeling the immune response since its pathogenesis has been well described at a molecular, cellular and organism level. L. monocytogenes invades macrophages, can escape into the cytoplasm and spread intercellularly. Due to the intracellular nature of infection, CD4 and CD8 T cells are important for control of infection and are essential for mediating protective immunity. On the other hand, the immune response during pulmonary B. anthracis infection has not been well examined. Inhalational anthrax is a rapidly progressing disease in which spores germinate within alveolar macrophages and then disseminate to the lymph nodes, causing an uncontrollable infection. Homologous virulence factors, such as phosphoslipases (PLCs) and hemolysins, may play similar roles in the pathogenesis of these two bacterial species. In these studies, we examine: (1) how antigen compartmentalization by L. monocytogenes can affect the ability of memory CD8 T cells to provide protective immunity, (2) the role of two virulence factors, listeriolysin O and phosphatidylcholine-preferring-PLC, in inducing FasL on T cells during L. monocytogenes infection, (3) the role of neutrophils during pulmonary B. anthracis infection, (4) the generation of an antigen-specific T cell response during pulmonary B. anthracis infection, and (5) the downmodulation of the immune response by B. anthracis phosphatidylinositol-specific-PLC during infection. These studies reveal how bacterial pathogens have evolved alongside their hosts to modulate immune responses to their own advantage

Characterization of Listeria monocytogenes Expressing Anthrolysin O and Phosphatidylinositol-Specific Phospholipase C from Bacillus anthracis

Two virulence factors of Listeria monocytogenes, listeriolysin O (LLO) and phosphatidylinositol-specific phospholipase C (PI-PLC), mediate escape of this pathogen from the phagocytic vacuole of macrophages, thereby allowing the bacterium access to the host cell cytosol for growth and spread to neighboring cells. We characterized their orthologs from Bacillus anthracis by expressing them in L. monocytogenes and characterizing their contribution to bacterial intracellular growth and cell-to-cell spread. We generated a series of L. monocytogenes strains expressing B. anthracis anthrolysin O (ALO) and PI-PLC in place of LLO and L. monocytogenes PI-PLC, respectively. We found that ALO was active at both acidic and neutral pH and could functionally replace LLO in mediating escape from a primary vacuole; however, ALO exerted a toxic effect on the host cell by damaging the plasma membrane. B. anthracis PI-PLC, unlike the L. monocytogenes ortholog, had high activity on glycosylphosphatidylinositol-anchored proteins. L. monocytogenes expressing B. anthracis PI-PLC showed significantly decreased efficiencies of escape from a phagosome and in cell-to-cell spread. We further compared the level of cytotoxicity to host cells by using mutant strains expressing ALO in combination either with L. monocytogenes PI-PLC or with B. anthracis PI-PLC. The results demonstrated that the mutant strain expressing the combination of ALO and B. anthracis PI-PLC caused less damage to host cells than the strain expressing ALO and L. monocytogenes PI-PLC. The present study indicates that LLO and L. monocytogenes PI-PLC has adapted for L. monocytogenes intracellular growth and virulence and suggests that ALO and B. anthracis PI-PLC may have a role in B. anthracis pathogenesis