Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis

Randall J. Olsen, Izabela Sitkiewicz, Ara A. Ayeras, Vedia E. Gonulal, Concepcion Cantu, Stephen B. Beres, Nicole M. Green, Benfang Lei, Tammy Humbird, Jamieson Greaver, Ellen Chang, Willie P. Ragasa, Charles A. Montgomery, Joiner Cartwright, Allison McGeer, Donald E. Low, Adeline R. Whitney, Philip T. Cagle, Terry L. Blasdel, Frank R. DeLeoJames M. Musser

Research output: Contribution to journalArticle

81 Scopus citations

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-nucleotidemutation 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 thatmtsR inactivationresults 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 ΔmtsR 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.

Original languageEnglish (US)
Pages (from-to)888-893
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number2
DOIs
StatePublished - 2010

Keywords

  • Group A streptococcus
  • Invasive infection
  • Molecular epidemiology of strain genotype patient phenotype relationships
  • Nonhuman primate

ASJC Scopus subject areas

  • General

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