Early evolutionary loss of the lipid A modifying enzyme PagP resulting in innate immune evasion in Yersinia pestis

Courtney E. Chandler, Erin M. Harberts, Mark R. Pelletier, Iyarit Thaipisuttikul, Jace W. Jones, Adeline M. Hajjar, Jason W. Sahl, David R. Goodlett, Aaron C. Pride, David A. Rasko, M. Stephen Trent, Russell E. Bishop, Robert K. Ernst

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Immune evasion through membrane remodeling is a hallmark of Yersinia pestis pathogenesis. Yersinia remodels its membrane during its life cycle as it alternates between mammalian hosts (37 °C) and ambient (21 °C to 26 °C) temperatures of the arthropod transmission vector or external environment. This shift in growth temperature induces changes in number and length of acyl groups on the lipid A portion of lipopolysaccharide (LPS) for the enteric pathogens Yersinia pseudotuberculosis (Ypt) and Yersinia enterocolitica (Ye), as well as the causative agent of plague, Yersinia pestis (Yp). Addition of a C16 fatty acid (palmitate) to lipid A by the outer membrane acyltransferase enzyme PagP occurs in immunostimulatory Ypt and Ye strains, but not in immune-evasive Yp. Analysis of Yp pagP gene sequences identified a single-nucleotide polymorphism that results in a premature stop in translation, yielding a truncated, nonfunctional enzyme. Upon repair of this polymorphism to the sequence present in Ypt and Ye, lipid A isolated from a Yp pagP+ strain synthesized two structures with the C16 fatty acids located in acyloxyacyl linkage at the 2′ and 3′ positions of the diglucosamine backbone. Structural modifications were confirmed by mass spectrometry and gas chromatography. With the genotypic restoration of PagP enzymatic activity in Yp, a significant increase in lipid A endotoxicity mediated through the MyD88 and TRIF/TRAM arms of the TLR4-signaling pathway was observed. Discovery and repair of an evolutionarily lost lipid A modifying enzyme provides evidence of lipid A as a crucial determinant in Yp infectivity, pathogenesis, and host innate immune evasion.

Original languageEnglish (US)
Pages (from-to)22984-22991
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 15 2020


  • Evolution
  • Immune evasion
  • Lipid A
  • Pathogenesis
  • Yersinia

ASJC Scopus subject areas

  • General


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