Engagement of the pathogen survival response used by group A Streptococus to avert destruction by innate host defense

Jovanka M. Voyich, Kevin R. Braughton, Daniel E. Sturdevant, Cuong Vuong, Scott D. Kobayashi, Stephen F. Porcella, Michael Otto, James M. Musser, Frank R. DeLeo

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Neutrophils are a critical component of human innate host defense and efficiently kill the vast majority of invading microorganisms. However, bacterial pathogens such as group A Streptococcus (GAS) successfully avert destruction by neutrophils to cause human infections. Relatively little is known about how pathogens detect components of the innate immune system to respond and survive within the host. In this study, we show that inactivation of a two-component gene regulatory system designated Ihk-Irr significantly attenuates streptococcal virulence in mouse models of soft tissue infection and bacteremia. Microarray analysis of wild-type and irr-negative mutant (irr mutant) GAS strains revealed that Ihk-Irr influenced expression of 20% of all transcripts in the pathogen genome. Notably, at least 11 genes involved in cell wall synthesis, turnover, and/or modification were down-regulated in the irr mutant strain. Compared with the wild-type strain, significantly more of the irr mutant strain was killed by human neutrophil components that destroy bacteria by targeting the cell envelope (cell wall and/or membrane). Unexpectedly, expression of ihk and irr was dramatically increased in the wild-type strain exposed to these same neutrophil products under conditions that favored cell envelope damage. We report a GAS mechanism for detection of innate host defense that initiates the pathogen survival response, in which cell wall synthesis is critical. Importantly, our studies identify specific genes in the pathogen survival response as potential targets to control human infections.

Original languageEnglish (US)
Pages (from-to)1194-1201
Number of pages8
JournalJournal of Immunology
Volume173
Issue number2
DOIs
StatePublished - Jul 15 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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