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dc.contributor.advisorChairperson, Graduate Committee: Benfang Leien
dc.contributor.authorStetzner, Zachary Williamen
dc.description.abstractGroup A Streptococcus (GAS) is a highly versatile pathogen that is able to colonize multiple locations on the body, resulting in numerous diseases such as mild pharyngitis and the potentially lethal necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS). The high mortality rates associated with severe invasive diseases are particularly concerning. GAS strains isolated from patients with severe invasive infections frequently display hypervirulence, but the basis for this hypervirulence is not fully understood. The objective of this project is to elucidate the underlying mechanism behind this hypervirulent phenotype in a serotype M3 STSS isolate, MGAS315. A comparative study of MGAS315 and a serotype M28 puerperal sepsis isolate, MGAS6180, revealed that MGAS315 has a substantially higher capacity to invade soft tissue and inhibit neutrophil recruitment than MGAS6180 in a murine model of subcutaneous infection. Deletion of the platelet-activating factor (PAF) acetylhydrolase gene sse reduced MGAS315 skin invasion and innate immune evasion. These results cannot be explained by the proposal that the hypervirulence of MGAS315 is due to the acquisition of additional prophage-encoding virulence factors. SsE is negatively regulated by the two-component regulatory system CovR/S, and MGAS315 has a CovS G457V mutation compared with the covS gene of the serotype M1 isolate MGAS2221. We hypothesize that the CovSG457V mutation is responsible for the hypervirulence of MGAS315. To test this hypothesis, the mutated covS gene in MGAS315 was replaced with wild-type covS, resulting in MGAS315wtcovS. The mRNA levels of CovR/S-controlled capsule synthase gene hasA and the IL-8 peptidase gene spyCEP in MGAS315wtcovS were 24% and 3% of those in MGAS315, respectively. Repairing the covS mutation in MGAS315 also reduced the PAF acetylhydrolase activity in the culture supernatant and SsE production as measured by western blotting analysis. These results indicate that the CovSG457V mutation enhanced the expression of CovR/S-controlled virulence factors. More importantly, repairing the CovS G457V mutation attenuated the innate immune evasion, skin evasion, and virulence during infection. Collectively, this work demonstrates the CovS G457V mutation increases virulence factor expression and enhances innate immune evasion, thereby contributing to the hypervirulence of MGAS315.en
dc.publisherMontana State University - Bozeman, College of Agricultureen
dc.subject.lcshStreptococcus pyogenesen
dc.subject.lcshVirulence (Microbiology)--Molecular aspectsen
dc.titleThe effect of a natural covS mutation on virulence factor expression and innate immune evasion in a hypervirulent strain of group A streptococcusen
dc.rights.holderCopyright 2013 by Zachary William Stetzneren
thesis.catalog.ckey2737190en, Graduate Committee: Joshua Obar; Mark T. Quinnen & Immunology.en

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