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An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections

Abstract

The role of host genetic factors in conferring predisposition or protection in infectious diseases has become evident. Infection with group A streptococci causes a wide spectrum of disease ranging from pharyngitis to streptococcal toxic shock syndrome. The release of inflammatory cytokines triggered by streptococcal superantigens has a pivotal role in invasive streptococcal disease. However, individuals infected with the same strain can develop very different manifestations. We report here that the immunogenetics of the host influence the outcome of invasive streptococcal infection, and demonstrate the underlying mechanism for these genetic associations. Specific human leukocyte antigen class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (P < 0.0001). We propose that human leukocyte antigen class II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.

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Figure 1: HLA class II haplotypes associated with outcomes of invasive GAS infections.
Figure 2: Responses of healthy individuals with risk, neutral or protective haplotypes to M1T1 SAgs.
Figure 3: Responses of convalescent patients to the SAgs produced by their isolate.
Figure 4: Proliferative and cytokine responses of matched pairs of convalescent patients.
Figure 5: Presentation of GAS SAgs by cells carrying SSD protective/predispositional haplotypes.
Figure 6: Presentation of GAS SAgs by cells carrying NF + SSD protective/predispositional haplotypes.

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Acknowledgements

We thank all infectious disease physicians in Canada who have contributed valuable samples and clinical information for this study; L. Trepski and the Ontario Streptococcal Study Group in Canada; and Y. Guédez of the Veterans Administration in Memphis. This work was supported by grants from the U.S. Veterans Administration Merit Award (M.K.), the National Institutes of Health (AI40198, M.K.) and the Swedish Medical Research Council (A.N.-T). The Ontario Streptococcal Study Group was originally started by funds from the Center for Disease Control.

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Correspondence to Malak Kotb.

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Kotb, M., Norrby-Teglund, A., McGeer, A. et al. An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat Med 8, 1398–1404 (2002). https://doi.org/10.1038/nm1202-800

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