title: Type IV pili-mediated secretion modulates Francisella virulence.
abstract: Francisella tularensis are the causative agent of the zoonotic disease, tularaemia. Among four F. tularensis subspecies, ssp. novicida (F. novicida) is pathogenic only for immunocompromised individuals, while all four subspecies are pathogenic for mice. This study utilized proteomic and bioinformatic approaches to identify seven F. novicida secreted proteins and the corresponding Type IV pilus (T4P) secretion system. The secreted proteins were predicted to encode two chitinases, a chitin binding protein, a protease (PepO), and a beta-glucosidase (BglX). The transcription of F. novicida pepO and bglX was regulated by the virulence regulator MglA. Intradermal infection of mice with F. novicida mutants defective in T4P secretion system or PepO resulted in enhanced F. novicida spread to systemic sites. Infection with F. novicida pepO mutants also resulted in increased neutrophil infiltration into the mouse airways. PepO is a zinc protease that is homologous to mammalian endothelin-converting enzyme ECE-1. Therefore, secretion of PepO likely results in increased production of endothelin and increased vasoconstriction at the infection site in skin that limits the F. novicida spread. Francisella human pathogenic strains contain a mutation in pepO predicted to abolish its secretion. Loss of PepO function may have contributed to evolution of highly virulent Francisellae.
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, University of Washington, Seattle, WA, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hager
authors.forename: Diana L
authors.initials: DL
authors.lastname: Bolton
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pelletier
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Brittnacher
authors.forename: Larry A
authors.initials: LA
authors.lastname: Gallagher
authors.forename: Rajinder
authors.initials: R
authors.lastname: Kaul
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Skerrett
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
authors.forename: Tina
authors.initials: T
authors.lastname: Guina
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003470:Culture Media / Q000378:metabolism; D036781:Fimbriae Proteins / Q000235:genetics* / Q000378:metabolism; D005603:Francisella / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D005816:Genetic Complementation Test; D016905:Gram-Negative Bacterial Infections / Q000382:microbiology; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009154:Mutation / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000382:microbiology; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D003470:Culture Media; D037521:Virulence Factors; D036781:Fimbriae Proteins; D045726:Metalloproteases