Genome-wide protective response used by group AStreptococcusto evade destruction by human polymorphonuclear leukocytes

Abstract

Group A Streptococcus (GAS) evades polymorphonuclear leukocyte (PMN) phagocytosis and killing to cause human disease, including pharyngitis and necrotizing fasciitis (flesh-eating syndrome). We show that GAS genes differentially regulated during phagocytic interaction with human PMNs comprise a global pathogen-protective response to innate immunity. GAS prophage genes and genes involved in virulence, oxidative stress, cell wall biosynthesis, and gene regulation were up-regulated during PMN phagocytosis. Genes encoding novel secreted proteins were upregulated, and the proteins were produced during human GAS infections. We discovered an essential role for the Ihk-Irr twocomponent regulatory system in evading PMN-mediated killing and promoting host-cell lysis, processes that would facilitate GAS pathogenesis. Importantly, the irr gene was highly expressed during human GAS pharyngitis. We conclude that a complex pathogen genetic program circumvents human innate immunity to promote disease. The gene regulatory program revealed by our studies identifies previously undescribed potential vaccine antigens and targets for therapeutic interventions designed to control GAS infections.

Oxidative stress response in Clostridium perfringens

“…This suggests that C. perfringens cells are protected from the oxidative burst of the macrophages. According to Voyich et al (2003), upregulation of oxidative stress genes, virulence genes, cell-wall biosynthesis genes and related regulatory genes is observed when group A streptococci evade polymorphonuclear leukocyte phagocytosis. The genes encoding the glutathione peroxidase, alkyl hydroperoxide reductase (etc.)…”

Toward a Genome-Wide Systems Biology Analysis of Host-Pathogen Interactions in Group A Streptococcus

“…53,54 Genes related to prophage, oxidative stress, cell-wall biosynthesis, virulence, and novel extracellular secreted proteins of unknown function were up-regulated during phagocytic interaction (Figure 3). Importantly, an essential role in immune evasion was discovered for the Ihk-Irr TCS using an isogenic mutant strain in which this gene regulatory system was inactivated.…”

“…However, GAS is relatively resistant to killing by these anti-bacterial components. 53,54,[61][62][63][64] Although progress has been made, the molecular basis for this resistance is incompletely understood. Two recent transcriptome-based studies shed new light on the gene regulation mechanisms used by GAS to avoid destruction by human PMNs.…”

“…Differences in survival were attributed to increased susceptibility of the irr-mutant strain to microbicidal components present within the PMN phagosome. 53,54 Thus, the Ihk-Irr TCS controls expression of genes that facilitate evasion of PMN-mediated bacterial killing, thereby assisting GAS survival and pathogenesis (Figure 4). Consistent with these findings, the irr gene is highly expressed in human GAS pharyngitis.…”

“…Several expression microarray studies have examined GAS, and extensive new information has been obtained about the nature and extent of changes in the pathogen's transcriptome in response to various perturbations. 28,[51][52][53][54][55][56] This global approach to understanding pathogenesis was facilitated by the information obtained from GAS genome sequencing projects, as described above. Initial studies used conventional spotted microarrays and focused on in vitro analysis, but more recently a custom Affymetrix high-density oligonucleotide array has been used for ex vivo and in vivo studies.…”