Contribution of Streptolysin O and Streptolysin S to Streptococcus pyogenes Infections in HLA-Transgenic Mice
Abstract
Streptococcus pyogenes is a human-specific bacterial pathogen that commonly colonizes the upper respiratory tract and skin, causing a wide variety of diseases ranging from pharyngitis to necrotizing fasciitis and toxic shock syndrome. S. pyogenes has a repertoire of secreted virulence factors that promote infection and evasion of the host immune system including the cytolysins streptolysin O (SLO) and streptolysin S (SLS). S. pyogenes does not naturally infect the upper respiratory tract of mice, although mice transgenic for MHC class II human leukocyte antigens (HLA) become highly susceptible. Here, we used HLA-transgenic mice to assess the role of both SLO and SLS during both nasopharyngeal and skin infection. Using S. pyogenes MGAS8232 as a model strain, we found that an SLS-deficient strain exhibited a 100-fold reduction in bacterial recovery from the nasopharynx and a 10-fold reduction in bacterial burden in the skin, whereas an SLO-deficient strain did not exhibit any infection defects in these models. Furthermore, depletion of neutrophils significantly restored the bacterial burden of the SLS-deficient bacteria in skin, but not in the nasopharynx. In mice nasally infected with wildtype S. pyogenes, there was a marked change in the localization of the tight junction protein ZO-1 at the site of infection, demonstrating damage to the nasal epithelium that was absent in mice infected with the SLS-deficient strain. Overall, we conclude that SLS is required for the establishment of nasopharyngeal and skin infection in HLA-transgenic mice by S. pyogenes MGAS8232, and we provide evidence that SLS contributes to nasopharyngeal infection through the localized destruction of nasal epithelium. Given the importance of SLS during S. pyogenes infections, we also set out to develop a vaccine targeting the SLS toxin. However, optimization of protein production and purification is still required. This work identifies SLS as a key virulence determinant and has the potential to guide the development of therapies to prevent and treat S. pyogenes infections by targeting SLS-induced pathogenesis.