Chlamydia trachomatis Lipopolysaccharide Evades the Canonical and Noncanonical Inflammatory Pathways To Subvert Innate Immunity

Abstract

<i>Chlamydia trachomatis</i> is the most common bacterial cause of sexually transmitted infections. <i>C. trachomatis</i> sexually transmitted infections are commonly asymptomatic, implying a pathogenic strategy for the evasion of innate inflammatory immune responses, a paradox as the <i>C. trachomatis</i> outer membrane contains lipopolysaccharide (LPS), a known potent agonist of inflammatory innate immunity. Here, we studied the ability of chlamydial LPS to activate the proinflammatory canonical and noncanonical inflammasome pathways in mouse bone marrow-derived macrophages (BMDM). We show, in comparison to <i>Escherichia</i><i>coli</i> LPS, that <i>C. trachomatis</i> LPS-treated BMDM produce significantly less IL-6, TNF, and type I interferon mRNA, indicating that downstream signaling through the canonical TLR4 myddosome and triffosome pathways was blocked. We confirmed this in <i>C. trachomatis</i> LPS-treated BMDM by showing the lack of NF-κB and IRF3 phosphorylation, respectively. Interestingly, <i>C. trachomatis</i> LPS bound CD14 and promoted its endocytosis; however; it did not promote efficient TLR4/MD-2 dimerization or endocytosis, known requirements for myddosome and triffosome signaling pathways. We further found that transfection of BMDM with <i>C. trachomatis</i> LPS did not cause pyroptotic cell ballooning, cytotoxicity, or IL-1β secretion, all characteristic features of noncanonical inflammasome activation. Western blotting confirmed that cytosolic <i>C. trachomatis</i> LPS failed to signal through caspase-11, as shown by the lack of gasdermin D, caspase-1, or IL-1β proteolytic cleavage. We propose that chlamydiae evolved a unique LPS structure as a pathogenic strategy to avoid canonical and noncanonical innate immune signaling and conclude that this strategy might explain the high incidence of asymptomatic infections.<b>IMPORTANCE</b><i>Chlamydia trachomatis</i> is the most common bacterial cause of sexually transmitted infections (STI). <i>C. trachomatis</i> STI are commonly asymptomatic, implying a pathogenic strategy for the evasion of innate inflammatory immune responses, a paradox as the <i>C. trachomatis</i> outer membrane contains lipopolysaccharide (LPS), a known potent agonist of inflammatory innate immunity. Here, we found that <i>C. trachomatis</i> LPS is not capable of engaging the canonical TLR4/MD-2 or noncanonical caspase-11 inflammatory pathways. The inability of <i>C. trachomatis</i> LPS to trigger innate immunity inflammatory pathways is related to its unique fatty acid structure. Evolutionary modification of the LPS structure likely evolved as a pathogenic strategy to silence innate host defense mechanisms. The findings might explain the high incidence of asymptomatic chlamydial genital infection.