The virulence of Group A Streptococcus (GAS) is due to multiple factors including the production of superantigens such as Streptococcus Pyrogenic Exotoxin A (SPEA). Superantigens activate the T-lymphocyte through a non-specific MHC-antigen presenting cell complex of which intercellular adhesion molecule-1 (ICAM-1) is a necessary component. We sought to determine the contribution of ICAM-1 in the host response to SPEA-producing and non-SPEA producing GAS.

Methods: C57BL/6J mice genetically deficient in ICAM-1 (-/-) and wild type mice of the same strain (+/+) were challenged via the flank with 107 organisms of either SPEA producing GAS (GAS+) or non-SPEA producing GAS (GAS-) in 14 separate experiments. All groups received intraperitoneal Actinomycin D immediately after bacterial challenge. Animals were scored for the presence of leg swelling, necrosis, conjunctivitis, pilorection, and decreased activity (clinical score 0-5). Blood cultures were obtained at 24 and 48 h. At 48 h, surviving animals were sacrificed. Histopathology was performed on 2 mice from each group. Sera was examined for the presence of IL-2 and IL-10 at 6, 12, and 24 h, and TNFα at 2, 4, and 8 h post challenge.

Results: The -/- animals had decreased mortality at 48 h as compared to +/+ animals when challenged with GAS+ (17/32, 53% vs 28/33, 88%; p<0.005) and with GAS- (11/33, 33% vs 21/33, 64%; p<0.01). The clinical scores at 24 and 48 h for the surviving animals from each group were evaluated for clinical significance using a two way ANOVA. The mean clinical scores between the -/- and the +/+ animals from either group innoculated with GAS+ or with GAS- were significant at 24 h (p<0.001, p<0.013) and at 48 h(p<0.018, p<0.001). Weight loss was similar in each group. There was no detectable circulating IL-2, IL-10, or TNFα in any of the groups. There was no significant difference in bacteremia between the groups. On histopathology, by 48 h all of the animals had evidence of hepatic injury including hemorrhage, vacuolization, and bland necrosis. The kidneys from all of the animals remained uninvolved. The dermis and muscle were involved with ulcer formation, edema, and necrosis.

Conclusion: Mice deficient in ICAM-1 are protected against both GAS+ and GAS- strains. The production of SPEA does not appear to contribute to the mortality associated with this GAS nonisogenic strain. It does appear to contribute to the overall virulence of GAS. Studies are underway in elucidating the mechanism of the pathogenesis of this GAS infection and the host response involved when deficient of ICAM-1.