title: Expression of Escherichia coli virulence usher protein attenuates wild-type Salmonella.
abstract: Generation of a live attenuated vaccine for bacterial pathogens often requires prior knowledge of the pathogen's virulence factors. We hypothesized an alternative approach of heterologous gene expression would make a wild-type (wt) pathogen more susceptible to host cell killing, thus, resulting in immunization. As proof of concept, the heterologous expression of enterotoxigenic E. coli (ETEC) colonization factor antigen I (CFA/I) was tested to attenuate Salmonella. The overexpression of CFA/I resulted in significant attenuation of wt Salmonella. In-depth studies revealed the attenuation depended on the co-expression of chaperone (CfaA) and usher (CfaC) proteins. Remarkably, the CfaAC-attenuated Salmonella conferred protection against wt Salmonella challenge. Mechanistic study indicated CfaAC made Salmonella outer membranes permeable, causing Salmonella to be vulnerable to host destruction. Thus, enhancing bacterial permeability via CfaAC represents an alternative method to attenuate pathogens despite the presence of unknown virulence factors.
authors.affiliation: Department of Immunology & Infectious Diseases, Montana State University, Bozeman, MT, USA.
authors.forename: Xinghong
authors.initials: X
authors.lastname: Yang
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Suo
authors.forename: Theresa
authors.initials: T
authors.lastname: Thornburg
authors.forename: Kathryn
authors.initials: K
authors.lastname: Holderness
authors.forename: Ling
authors.initials: L
authors.lastname: Cao
authors.forename: Timothy
authors.initials: T
authors.lastname: Lim
authors.forename: Nancy
authors.initials: N
authors.lastname: Walters
authors.forename: Laura
authors.initials: L
authors.lastname: Kellerman
authors.forename: Linda
authors.initials: L
authors.lastname: Loetterle
authors.forename: Recep
authors.initials: R
authors.lastname: Avci
authors.forename: David W
authors.initials: DW
authors.lastname: Pascual
mesh_terms: D000818:Animals; D002460:Cell Line; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000276:immunology; D005260:Female; D036781:Fimbriae Proteins / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics* / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology*; D012486:Salmonella typhimurium / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics* / Q000276:immunology
chemical_list: C574723:CfaC protein, E coli; D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; D037521:Virulence Factors; C022924:colonization factor antigens; D036781:Fimbriae Proteins