Doctor of Philosophy
Microbiology and Immunology
Dr. S. M. Mansour Haeryfar
Toxic shock syndrome (TSS) is an acute, potentially fatal condition characterized by high-grade fever, hypotensive shock and systemic inflammation. It is caused by exposure to staphylococcal and streptococcal superantigens (SAgs), which can activate up to 50% of T cells resulting in a hyperinflammatory ‘cytokine storm’ within hours. This inflammatory cascade progresses to a life-threatening illness with alarming rapidity, and SAg-exposed individuals can develop multi-organ failure within hours of onset of symptoms. However, there are currently no available treatments that efficiently mitigate the cytokine storm, which drives TSS immunopathology. Therefore, identifying and understanding the critical components underlying this process should hold the key to designing effective therapeutics to reduce TSS severity. In this thesis, I have utilized a clinically relevant humanized HLA-DR4 transgenic (DR4tg) mouse model of TSS to reveal the previously unrecognized roles of three rapid host responses in the initiation or control of the cytokine storm. First, genetic and antibody-mediated depletion of invariant natural killer T (iNKT) cells in DR4tg mice show that iNKT cells are pathogenic in TSS and contribute to the cytokine storm. Targeting iNKT cell responses with the T helper type-2 (Th2)-polarizing glycolipid agonist OCH also reduces TSS morbidity and mortality. Second, I found that granulocytic myeloid-derived suppressor cells (MDSCs) are rapidly recruited to the liver of DR4tg mice during TSS. These hepatic MDSCs potently suppress SAg-induced T cell responses and may therefore mitigate tissue injury in TSS. Lastly, I define the rapid production of interleukin-17A (IL-17A) by effector memory T cells as a novel mechanism promoting immunopathology in TSS. Blockade of IL-17A signaling in human blood mononuclear cells reduces the expression of multiple inflammatory mediators of TSS, suggesting that IL-17A contributes to the cytokine storm. Importantly, the treatment of DR4tg mice with an IL-17A-neutralizing antibody attenuates TSS-induced tissue damage, morbidity and mortality. Collectively, the results presented in this thesis delineate the novel contributions of iNKT cells, MDSCs and IL-17A to the early phase of TSS pathogenesis. Furthermore, my findings suggest that therapeutic approaches targeting iNKT cells or IL-17A responses may be effective in reducing TSS mortality.
Szabo, Peter Anthony, "Rapid Regulatory and Effector Immune Responses in Toxic Shock Syndrome" (2017). Electronic Thesis and Dissertation Repository. 4450.
Available for download on Monday, April 01, 2019