R eceptor interacting protein‐2 contributes to host defense against A naplasma phagocytophilum infection

The G ram‐negative obligate intracellular bacterium A naplasma phagocytophilum is the causative agent of human granulocytic anaplasmosis ( HGA ), an emerging tick‐borne infectious disease occurring worldwide. HGA is generally self‐limiting; however, the underlying mechanisms, particularly the innate immune pathways that mediate the immune clearance of A . phagocytophilum , are less understood. We herein report an unexpected role for Receptor interacting protein‐2 ( R ip2), the adaptor protein for the N od‐like receptors ( NLR s), N od1/ N od2, in the host immune response against A . phagocytophilum infection. Although A . phagocytophilum genome is reported to lack the genes encoding the known ligands of N od1 and N od2, its infection upregulated the transcription of R ip2 in human primary neutrophils. Our results revealed that R ip2‐deficient mice had significantly higher bacterial load than wild‐type controls throughout the infection period. In addition, the R ip2‐deficient mice took strikingly longer duration to clear A . phagocytophilum infection. Detailed analysis identified that interferon gamma ( IFN γ) and interleukin ( IL )‐18 but not IL ‐12, macrophage inflammatory protein‐2, and KC response were diminished in A . phagocytophilum ‐challenged R ip2‐deficient mice. Together, these results revealed that R ip2 plays important roles in the immune control of A . phagocytophilum and may contribute to our understanding of the host response to R ickettsiales.