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The Role of the MHC on Resistance to Group A Streptococci in Mice¹

Oliver Goldmann^*, Andreas Lengeling, Jens Böse, Helmut Bloecker, Robert Geffers, Gursharan S. Chhatwal^¶ and Eva Medina^2,*

^* Infection Immunology Group and Infection Genetics Group, Department of Microbial Pathogenesis and Vaccine Research, Department of Genome Analysis, Array Facility, and ^¶ Microbial Pathogenesis Group, Department of Microbial Pathogenesis and Vaccine Research, Gesellschaft fur Biotechnologishe Forschung-German Research Center for Biotechnology, Braunschweig, Germany

The severity of infection with Streptococcus pyogenes is strongly influenced by the host’s genetics. This observation extends to the murine model of streptococcal infection, where the background of the mouse strain determines the infection outcome (BALB/c are resistant, whereas C3H/HeN are susceptible). To determine the extent to which the MHC complex (H2) contributed to diseases susceptibility, the response to S. pyogenes of congenic BALB mice from a resistant background (BALB/c), but carrying the H2^k region of susceptible C3H/HeN mice (BALB/k), was examined. BALB/k were as susceptible as the H2 donor strain (C3H/HeN). Linkage analysis performed in F₂ backcross ([BALB/c x C3H/HeN] x BALB/c) mice confirmed the presence of a susceptibility locus within the H2 region on proximal chromosome 17. The possibility that modulation of T cell responses to streptococcal superantigens (GAS-SAgs) by different H2 haplotypes may influence disease severity was examined. BALB/k exhibited a significantly stronger response at the level of cell proliferation and cytokine production to GAS-SAgs than did BALB/c mice. However, the fact that T cell-deficient SCID-C3H/HeN mice also exhibited a susceptible phenotype suggests a more important contribution of innate effector cells to disease susceptibility. Lower transcriptional levels of certain inflammation-related regulatory genes located on chromosome 17 were detected in macrophages from susceptible than in those from resistant mice in response to infection. These results suggest that susceptibility to S. pyogenes may be associated with an altered transcription of specific genes that may compromise the endogenous regulatory processes controlling the inflammatory cascade and favor the progression to sepsis.

This article has been cited by other articles:

				O. Goldmann, M. von Kockritz-Blickwede, C. Holtje, G. S. Chhatwal, R. Geffers, and E. Medina Transcriptome Analysis of Murine Macrophages in Response to Infection with Streptococcus pyogenes Reveals an Unusual Activation Program Infect. Immun., August 1, 2007; 75(8): 4148 - 4157. [Abstract] [Full Text] [PDF]