Lipopolysaccharide (LPS) is highly immunostimulatory, yet it is evolutionarily conserved among many obligate intracellular bacteria for unknown reasons. We report a forward genetic screen to identify factors required for survival of the tick-borne obligate cytosolic pathogen Rickettsia parkeri in primary macrophages. The most critical factors were WecA and RmlD, which synthesize O-antigen, the outermost layer of LPS. wecA and rmlD mutants grew at similar rates to wild type bacteria in epithelial cells, yet in macrophages they were targeted by guanylate binding proteins (GBPs) and they hyperactivated inflammasomes. Survival of O-antigen-deficient mutants was restored >1,000-fold in macrophages lacking Caspases-1 and -11, interferon signaling, and nitric oxide production, suggesting a multifaceted role for O-antigen in protecting against innate immunity. O-antigen was essential for causing disease in mice and protected R. parkeri against complement in vitro. Despite O-antigen being known as a major target of antibodies, mice immunized with O-antigen-deficient mutants were protected from a lethal rechallenge, suggesting that protection can be elicited independently of O-antigen-targeting antibodies. Together, these findings help resolve a paradox as to why obligate cytosolic bacteria evolutionarily maintain LPS despite it being immunostimulatory, which is that it serves as a multifunctional shield against innate immunity.
Sun, H., Guzman, A. A., Burke, T. P.
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