Significance Immune evasion is a hallmark of Yersinia pestis pathogenesis, including loss of pathogen-associated patterns recognized by Toll-like receptors. During its life cycle, Y. pestis alternates between mammalian hosts and arthropod transmission vectors and concurrently remodels its membrane, specifically modifying the structure of the lipid A portion of its lipopolysaccharide recognized by TLR4-MD2. Genomic analysis identified a single-nucleotide polymorphism that results in a premature stop in translation of the lipid A acyltransferase pagP , resulting in synthesis of a stealthy, hypoacylated lipid A structure absent in other Yersiniaceae. This provides evidence of lipid A as a crucial determinant in Y. pestis infectivity, pathogenesis, and host innate immune evasion and represents one of the earliest identified adaptations of Y. pestis from Yersinia pseudotuberculosis .