title: Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis.
abstract: Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species, but there is remarkably little information bearing on how they alter bacterial virulence. We recently discovered a single-nucleotide mutation in the group A Streptococcus genome that is epidemiologically associated with decreased human necrotizing fasciitis ("flesh-eating disease"). Working from this clinical observation, we find that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. Expression microarray analysis revealed that mtsR inactivation results in overexpression of PrsA, a chaperonin involved in posttranslational maturation of SpeB, an extracellular cysteine protease. Isogenic mutant strains that overexpress prsA or lack speB had decreased secreted protease activity in vivo and recapitulated the necrotizing fasciitis-negative phenotype of the DeltamtsR mutant strain in mice and monkeys. mtsR inactivation results in increased PrsA expression, which in turn causes decreased SpeB secreted protease activity and reduced necrotizing fasciitis capacity. Thus, a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis. Our discovery has broad implications for the confluence of population genomics and molecular pathogenesis research.
authors.affiliation: Center for Molecular and Translational Human Infectious Disease Research, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.forename: Izabela
authors.initials: I
authors.lastname: Sitkiewicz
authors.forename: Ara A
authors.initials: AA
authors.lastname: Ayeras
authors.forename: Vedia E
authors.initials: VE
authors.lastname: Gonulal
authors.forename: Concepcion
authors.initials: C
authors.lastname: Cantu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Beres
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Green
authors.forename: Benfang
authors.initials: B
authors.lastname: Lei
authors.forename: Tammy
authors.initials: T
authors.lastname: Humbird
authors.forename: Jamieson
authors.initials: J
authors.lastname: Greaver
authors.forename: Ellen
authors.initials: E
authors.lastname: Chang
authors.forename: Willie P
authors.initials: WP
authors.lastname: Ragasa
authors.forename: Charles A
authors.initials: CA
authors.lastname: Montgomery
authors.forename: Joiner
authors.initials: J
authors.lastname: Cartwright
authors.forename: Allison
authors.initials: A
authors.lastname: McGeer
authors.forename: Donald E
authors.initials: DE
authors.lastname: Low
authors.forename: Adeline R
authors.initials: AR
authors.lastname: Whitney
authors.forename: Philip T
authors.initials: PT
authors.lastname: Cagle
authors.forename: Terry L
authors.initials: TL
authors.lastname: Blasdel
authors.forename: Frank R
authors.initials: FR
authors.lastname: DeLeo
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D019115:Fasciitis, Necrotizing / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D014644:Genetic Variation; D006801:Humans; D008252:Macaca fascicularis / Q000382:microbiology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012703:Serotyping; D012772:Shock, Septic / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000235:genetics; D015854:Up-Regulation; D014774:Virulence / Q000235:genetics*