MOLECULAR ANALYSIS OF THE ROLE OF THE GROUP-A STREPTOCOCCAL CYSTEINE PROTEASE, HYALURONIC-ACID CAPSULE, AND M-PROTEIN IN A MURINE MODEL OF HUMAN INVASIVE SOFT-TISSUE INFECTION

Human invasive soft-tissue infections caused by group A Streptococcus are associated with significant morbidity and mortality. To investigat e the pathogenesis of these serious infections, we characterized the h ost response to bacterial challenge with an M-type 3 isolate recovered from a patient with necrotizing fasciitis, or with isogenic gene repl acement mutants deficient in cysteine protease, hyaluronic acid capsul e, or M protein in a murine model of human invasive soft-tissue infect ion. Animals challenged with the wild-type or cysteine protease-defici ent strain developed spreading tissue necrosis at the site of inoculat ion, became bacteremic, and subsequently died. Histopathologic examina tion of the necrotic lesion revealed bacteria throughout inflamed subc utaneous tissue. Arterioles and venules in the subcutaneous layer were thrombosed and the overlying tissue was infarcted. In contrast, anima ls challenged with either an acapsular or M protein-deficient mutant d eveloped a focal area of tissue swelling at the site of inoculation wi thout necrosis or subsequent systemic disease. Histopathologic examina tion of the soft-tissue lesion demonstrated bacteria confined within a well-formed subcutaneous abscess. We conclude that the group A strept ococcal hyaluronic acid capsule and M protein, but not the cysteine pr otease, are critical for the development of tissue necrosis, secondary bacteremia, and lethal infection in a murine model of human necrotizi ng fasciitis.