Breaking down barriers: hGBP1 acts as an LPS-binding surfactant to disrupt the bacterial outer membrane | New Voices in Infection Biology

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Talk abstract:

The enteric human-adapted bacterial pathogen Shigella flexneri induces acute intestinal infections with symptoms ranging from mild diarrhea to life-threatening dysentery. Following invasion of the colonic epithelium, Shigella enters the host cell cytosol and uses actin-based motility to enter neighboring host cells via direct cell-to-cell spread. This dissemination strategy shields Shigella from extracellular host defenses but at the same time exposes Shigella to cell-autonomous immune programs guarding the host cell cytosol. We and others recently discovered such an intracytosolic host defense program: we found that the interferon-inducible human guanylate binding protein 1 (hGBP1) co-localizes with cytosolic Shigella and prevents the formation of Shigella ‘actin-tails’ required for bacterial cell-to-cell spread. Countering this human defense Shigella evolved the secreted virulence factor IpaH9.8 as a potent hGBP1 antagonist, allowing Shigella to partly overcome hGBP1-mediated host defense. While our previous studies led to the discovery of hGBP1-mediated restriction of actin-based Shigella motility, the underlying mechanisms had remained undefined. In this seminar I will report on our recent mechanistic investigations revealing that hGBP1 targets Shigella and other gram-negative bacteria by binding directly to the outer membrane. We found that hGBP1 not only binds to but also clusters outer membrane component lipopolysaccharide (LPS). Interactions of hGBP1 with the outwards facing LPS O-antigen chains disrupt the integrity of the outer membrane and lead to bacterial lysis, recruitment and activation of LPS-sensor caspase-4, and interference with the function of Shigella’s outer membrane protein IcsA essential for the formation ‘actin tails’ and cytosolic motility. By identifying hGBP1 as an LPS-binding surfactant our studies provide a mechanistic explanation for hGBP1's pleiotropic antibacterial functions.