Skin transcriptomics reveals novel insights into pathophysiological mechanisms in humanized mice models of Group A Streptococcal Necrotizing Soft Tissue Infections

Abstract Despite prompt surgical debridement, clindamycin treatment with adjunct intravenous immunoglobulin and hyperbaric oxygen therapies, Necrotizing Soft Tissue Infections (NSTI) caused by Group A Streptococcus (GAS) bacteria progress rapidly into deeper layers of tissues, fascia, or muscle, portending significant morbidity and mortality. Our previous findings strongly support a role for host genetic factors, specifically, polymorphisms in HLA-Class II alleles in driving differential disease severity and NSTI outcomes. To facilitate a better understanding of pathophysiological mechanisms underlying NSTI, this study used a combined network and pathway analysis of the transcriptome data of GAS infected skin lesions from transgenic mice expressing human HLA-II alleles associated with varying susceptibility to NSTI. Our data analysis not only reaffirmed known modulators of NSTI susceptibility but revealed novel transcription factors and signaling pathways unique to immune functions. From these data we predict potential mechanisms by which GAS adapts in previously unidentified host niches. Our findings also provide new insights into the consequences of these extreme adaptations of GAS in the host during NSTI.