Mechanisms of immune evasion by Group A Streptococcus during skin infection

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Infections by Group A Streptococcus (GAS), or Streptococcus pyogenes, represent a global health concern (Carapetis et al., 2005). They range from mild skin or throat infections to severe invasive diseases with potentially fatal outcome. Post-infectious complications such as acute rheumatic fever (ARF), rheumatic heart disease (RHD) and kidney diseases also cause serious health problems. The burden of GAS disease is disproportionately high in socio-economically disadvantaged groups, including the indigenous communities in Australia. The fact that there is no vaccine available (Pandey et al., 2012) emphasises the need to better understand GAS pathogenesis as well as immune responses during infection. In this proposal, I focus on NS88.2, a clinical isolate that was obtained from a patient with bacteraemia in the Northern Territory (McKay et al., 2004). Isolates from invasive infections often have mutations in their covS or covR genes, which encode the control of virulence regulatory sensor kinase (CovR/S) system (Maamary et al., 2010). The CovR/S system regulates up to 15% of GAS genes in response to environmental cues. NS88.2 contains a mutation in covS, which Dr. Sanderson-Smith has previously succeeded in repairing to produce an isogenic strain, termed NS88.2rep, with reduced virulence (Sanderson-Smith et al., 2008). This pair of bacterial strains is therefore a unique resource for studying GAS pathogenesis in vivo. In preliminary work, it was found that even a very low dose of NS88.2, injected intradermally, causes a fatal disease in mice, characterised by systemic bacterial dissemination. In contrast, NS88.2rep is cleared effectively by the innate immune system in the skin, and, hence, does not cause lethal disease. The flow cytometric and microscopic studies, both in vitro and in vivo, suggest that while NS88.2rep is efficiently phagocytosed, NS88.2 evades neutrophil uptake. These results suggest that the covS mutation enables NS88.2 to circumvent attack by neutrophils.Objective: In this application, I will dissect the immuno-evasive properties of NS88.2 using molecular, immunologic and intravital imaging approaches. I will thus obtain fundamental insight into how this important human pathogen evades host immunity to cause disease.Hypothesis: NS88.2 interferes with neutrophil uptake during skin infection in vivo, enabling rapid disseminationAim 1. Determine how NS88.2 evades the local neutrophil response in the skinAim 2. Determine how NS88.2 disseminates from the skin to the blood