MyD88 suppresses IL-10 and IL-17 production in response to obligate intracellular Ehrlichia infection

Abstract

Abstract Ehrlichia is an obligate intracellular gram negative bacterium that target macrophages, and causes the potentially fatal human monocytic ehrlichiosis (HME). In murine models of fatal ehrlichiosis (FE), Ixodes ovatus Ehrlichia (IOE) inhibits autophagy, suppresses protective acquired immunity, and causes immunopathology and toxic shock syndrome. Innate Ehrlichia detection by TLR2 mediates host resistance, while NOD2 signaling confers host susceptibility to FE. Recently, we have shown that deficiency of type I interferon receptor (IFNaR) phenocopy NOD2 deficiency in IOE-infected mice, implying a contribution of both NOD2-IFNaR pathways to susceptibility to FE. However, how TLR2 mediates protective function against Ehrlichia is not clearly defined. Here, we investigated the role of MyD88, the main adaptor molecule for the TLRs in host response to virulent IOE using MyD88 knockout mice (MyD88−/−). Our data showed that, MyD88−/− mice have an impaired bacterial clearance, increased liver injury, and a heightened mortality when compared to infected wild type (WT) mice. Increased bacterial load in MYD88−/− mice correlates with decreased levels of TNF-α in both in vivo and in vitro {serum and IOE- infected bone marrow-derived macrophages (BMM)}, and increased frequency of splenic CD4+ T cells producing IL-10 and IL-17. Protective anti-Ehrlichia immunity and minimal pathology in WT mice infected with low virulent Ehrlichia species correlates with a high Th1 response, but a low frequency of IL-10 and IL-17 producing splenic T cells, suggesting that IL-10 and IL-17 may play pathogenic roles in host defense against Ehrlichia. Together these data suggest that MYD88 plays a protective role in ehrlichiosis via suppression of IL-10 and IL-17.