The overall goal of the present application is to explore the way specific host genetic factors and specific bacterial virulence determinants interact together to influence the outcome of an important infectious disease. This paradigm is critical to explain the wide variety of potential outcomes that occur when a human host encounters a potentially pathogenic organism like Group A streptococcus (GAS), from asymptomatic colonization to mild infection to severe morbidity or mortality. The model we have developed studies GAS-induced severe systemic disease (SSD; the bacterial superantigens (SAgs) that are key players in eliciting SSD; and the host factors involved are the HLA class II molecules that present the SAgs to T cells. The pathogenic link of the host genetic and bacterial virulence factors is clear, since the HLA molecules are receptors for SAgs, presenting them to the TCR and transmitting biochemical signals into APCs. We found that the host immunogenetic makeup influences the clinical outcome of invasive GAS disease. Specific HLA class II haplotypes conferred strong protection from the severe forms of the invasive disease, while others increased the risk for SSD. We also determined the underlying mechanism for these genetic associations by demonstrating that the presentation of Strep SAgs by the class II DRB1( 1501/DQB1*0602 haplotype, which was strongly associated with protection from SSD (P=0.0007), elicited significantly lower inflammatory responses as compared to their presentation by either risk or neutral haplotypes (P<0.0001). Patients with this protective haplotype mounted significantly reduced responses to the Strep SAgs (low responders) and were less likely to develop SSD. By contrast patients who lacked this protective haplotypes or had the DRB1*14/DQB1*0503 high risk haplotype were high responders to the Strep SAgs and were more likely to develop SSD. Our working hypothesis is that HLA class II association with risk/protection from SSD is the same for patients with invasive infections caused by particular GAS serotypes that are commonly isolated from invasive GAS infections and that share a similar SAg repertoire. The robust nature of our model is manifested in our initial identification human HLA haplotypes associated with high-risk and protection against GAS associated SSD. In this application, our combined bacterial and mammalian genetic approach will allow identification of how specific GAS SAg/human HLA combinations determine risk for a particular disease outcome. It is our hope that these results will inform the future design and application of specific therapeutic and vaccine strategies against GAS infection, and serve as a model for investigating the complex pathogenesis of other human bacterial infections.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Bacteriology and Mycology Subcommittee 2 (BM)
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Taylor, Christopher E,
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University of Tennessee Health Science Center
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Nooh, Mohammed M; Nookala, Suba; Kansal, Rita et al. (2011) Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care. J Immunol 186:3156-63
Kansal, Rita G; Datta, Vivekanand; Aziz, Ramy K et al. (2010) Dissection of the molecular basis for hypervirulence of an in vivo-selected phenotype of the widely disseminated M1T1 strain of group A Streptococcus bacteria. J Infect Dis 201:855-65
Aziz, Ramy K; Kansal, Rita; Aronow, Bruce J et al. (2010) Microevolution of group A streptococci in vivo: capturing regulatory networks engaged in sociomicrobiology, niche adaptation, and hypervirulence. PLoS One 5:e9798
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Nooh, Mohammed M; El-Gengehi, Nagala; Kansal, Rita et al. (2007) HLA transgenic mice provide evidence for a direct and dominant role of HLA class II variation in modulating the severity of streptococcal sepsis. J Immunol 178:3076-83
Nooh, Mohammed M; Aziz, Ramy K; Kotb, Malak et al. (2006) Streptococcal mitogenic exotoxin, SmeZ, is the most susceptible M1T1 streptococcal superantigen to degradation by the streptococcal cysteine protease, SpeB. J Biol Chem 281:35281-8
Thulin, Pontus; Johansson, Linda; Low, Donald E et al. (2006) Viable group A streptococci in macrophages during acute soft tissue infection. PLoS Med 3:e53
Ohuoba, Esobe F; Kansal, Rita G; Hayden, Randall T et al. (2006) Failure of viridans group streptococci causing bacteremia in pediatric oncology patients to express superantigens. J Pediatr Hematol Oncol 28:627-9

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