Differential contribution of IL-18 receptor beta to protective immunity and immunopathology during infection with intracellular bacteria (134.18)

Abstract

IL-18 has been shown to play a critical role in cytokine-induced organ failure during endotoxic shock. Human monocytotropic ehrlichiosis (HME) is a tick-borne infectious disease caused by E. chaffeenesis. HME is modeled in B6 mice using Ehrlichia muris (EM) that cause mild disease, and Ixodes ovatus Ehrlichia (IOE) that cause fatal shock-like syndrome. As Ehrlichia-induced septic shock and tissue injury is associated with increased IL-18 production, we examined the effect of blocking IL-18 signaling via IL-18Rβ on host defense & immune responses following sublethal (EM) and lethal (IOE) infection. Compared to IOE-infected isotype controls, in vivo IL-18Rβ neutralization in IOE-infected mice decreased bacterial burden, increased frequency of IFN-γ producing NK and NKT cells and enhanced production of TNF-α by T and non T cells on day 2 post-infection. On day 7 post-infection, blocking IL-18Rβ in lethally infected mice did not significantly influence the acquired pathogenic immune responses compared to lethally-infected isotype controls. Interestingly, blocking IL-18Rβ in the EM-infected mice increased bacterial burden, which was associated with suppressed early production of TNF-α and IFN-γ by different cell subsets compared to EM-infected isotype controls. These data suggest that IL-18Rβ may play dual protective and pathogenic roles in sublethal and lethal ehrlichial infection, respectively, through regulation of IFN-γ and TNF-α production by different innate cell subsets.