Yersinia pestis, the etiological agent of plague, persists in an enzootic cycle involving mammals and fleas, requiring constant outer membrane (OM) adaptation to disparate host environments. One such pathway involves the glycine zipper 2TM domain-containing protein SlyB, a central component of the OM stress response and PhoPQ virulence pathway. While the OM is critical for virulence, the role of the OM lipoprotein SlyB in Y. pestis ecology and pathogenesis remains unknown. We show by phylogenetic analyses that slyB paralogs expanded in environmental bacteria, whereas the canonical slyB gene was under negative selective pressure during Y. pestis speciation from Yersinia pseudotuberculosis. Using rodent and flea infection models recapitulating Y. pestis natural history, we demonstrate that SlyB is specifically required to resist the mammalian immune system at 37 degrees Celsius, including neutrophil-mediated antimicrobial activity during lymph node colonization, but is dispensable in septicemic plague in rodents. Strikingly, SlyB is not required for flea colonization and resistance to the antimicrobial-peptide-based immunity of arthropods at lower temperatures. SlyB-dependent OM stress tolerance reveals a mechanism by which Y. pestis establishes bubonic plague, in line with its critical lipopolysaccharide structural switch. Our findings identify SlyB as an evolutionarily fine-tuned component of the Y. pestis envelope that mediates immune escape upon infection of mammalian hosts through maintenance of structural integrity.
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