Roles of Chaperone/Usher Pathways of Yersinia pestis in a Murine Model of Plague and Adhesion to Host Cells

Abstract

Yersinia pestis and many other Gram-negative pathogenic bacteria use the chaperone/usher (CU) pathway to assemble virulence-associated surface fibers termed pili or fimbriae. Y. pestis has two well-characterized CU pathways: the caf genes coding for the F1 capsule and the psa genes coding for the pH 6 antigen. The Y. pestis genome contains additional CU pathways that are capable of assembling pilus fibers, but the roles of these pathways in the pathogenesis of plague are not understood. We constructed deletion mutations in the usher genes for six of the additional Y. pestis CU pathways. The wild-type (WT) and usher deletion strains were compared in the murine bubonic (subcutaneous) and pneumonic (intranasal) plague infection models. Y. pestis strains containing deletions in CU pathways y0348-0352, y1858-1862, and y1869-1873 were attenuated for virulence compared to the WT strain by the intranasal, but not subcutaneous, routes of infection, suggesting specific roles for these pathways during pneumonic plague. We examined binding of the Y. pestis WT and usher deletion strains to A549 human lung epithelial cells, HEp-2 human cervical epithelial cells, and primary human and murine macrophages. Y. pestis CU pathways y0348-0352 and y1858-1862 were found to contribute to adhesion to all host cells tested, whereas pathway y1869-1873 was specific for binding to macrophages. The correlation between the virulence attenuation and host cell binding phenotypes of the usher deletion mutants identifies three of the additional CU pathways of Y. pestis as mediating interactions with host cells that are important for the pathogenesis of plague.

Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane

“…The chaperone/usher (CU) pathway is a conserved secretion system dedicated to the biogenesis of pili in Gram-negative bacteria (1,(6)(7)(8), including pathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Yersinia pestis, Acinetobacter baumannii, and intestinal and extraintestinal pathogenic Escherichia coli (9)(10)(11)(12)(13)(14)(15)(16). Pilus biogenesis by the CU pathway requires two specialized assembly components: a periplasmic chaperone and an integral outer membrane (OM) assembly and secretion platform termed the usher.…”

Environmental Regulation of Yersinia Pathophysiology

“…This system is encoded on a virulence plasmid common to all three human Yersinia pathogens, and contributes two major virulence traits to Yersinia —anti-phagocytic and immunosuppression activities (Plano and Schesser, 2013 ). Several additional protein secretion systems, especially including a chromosomal T3SS, a T2SS, multiple T5SSs, and T6SSs as well as chaperone-usher systems, are predicted in the genomes of pathogenic Yersinia (Yen et al, 2008 ), and the functionality of some of these have been verified experimentally (Haller et al, 2000 ; Venecia and Young, 2005 ; Yen et al, 2007 ; Felek et al, 2008 , 2011 ; Lawrenz et al, 2009 ; Robinson et al, 2009 ; Hatkoff et al, 2012 ; Lenz et al, 2012 ; Pisano et al, 2012 ; Seo et al, 2012 ; Von Tils et al, 2012 ; Lane et al, 2013 ; Walker et al, 2013 ; Nair et al, 2015 ; Wang et al, 2015 ; Figure 1 ).…”

Not just an antibiotic target: Exploring the role of type I signal peptidase in bacterial virulence

“…The chaperone-usher (C/U) pathway, which relies on SPase processing for all of its substrates, is responsible for the assembly of at least 30 different types of surface fibers that are vital for the initial stage of infection for pathogens such as E. coli, 133,134 Acinetobacter baumannii, 135 Salmonella enterica serovars, 136–138 Yersinia species, 139,140 H. influenzae, 141 P. aeruginosa, 142 Bordetella pertussis, 143 K. pneumoniae, 144 and Proteus mirabilis . 145,146 These surface fibers function to provide adhesion to host cells, evade the immune response, and contribute to biofilm formation.…”