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

Autor:	Chandler CE; Department of Microbial Pathogenesis, University of Maryland, Baltimore, MD 21201., Harberts EM; Department of Microbial Pathogenesis, University of Maryland, Baltimore, MD 21201., Pelletier MR; Department of Microbial Pathogenesis, University of Maryland, Baltimore, MD 21201., Thaipisuttikul I; Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 10700., Jones JW; Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201., Hajjar AM; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195., Sahl JW; Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011., Goodlett DR; Department of Microbial Pathogenesis, University of Maryland, Baltimore, MD 21201.; International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland 80-822., Pride AC; Department of Molecular Biosciences, University of Texas, Austin, TX 78712., Rasko DA; Institute for Genome Sciences, University of Maryland, Baltimore, MD 21201., Trent MS; Department of Infectious Diseases, University of Georgia, Athens, GA 30602., Bishop RE; Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada L8S4L8., Ernst RK; Department of Microbial Pathogenesis, University of Maryland, Baltimore, MD 21201; rkernst@umaryland.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Sep 15; Vol. 117 (37), pp. 22984-22991. Date of Electronic Publication: 2020 Aug 31.
DOI:	10.1073/pnas.1917504117
Abstrakt:	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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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