HLA-II-dependent neuroimmune changes in Group A Streptococcal Necrotizing Fasciitis

Introduction Streptococcus pyogenes (Group A Streptococcus, GAS) bacteria cause a spectrum of human diseases ranging from self-limiting pharyngitis and mild uncomplicated skin infections (impetigo, erysipelas, cellulitis) to highly morbid and rapidly invasive life-threatening infections such as streptococcal toxic shock syndrome and necrotizing fasciitis (NF). HLA-Class II allelic polymorphisms are linked with differential outcomes and severity of GAS infections. The dysregulated immune response and peripheral cytokine storm elicited due to invasive GAS infections increase the risk for toxic shock and multiple organ failure in genetically susceptible individuals. We hypothesized that while the host immune mediators regulate the immune responses against peripheral GAS infections, these interactions may simultaneously trigger neuropathology and, in some cases, induce persistent alterations in the glial phenotypes. Here we studied the consequences of peripheral GAS skin infection on the brain in an HLA-II transgenic mouse model of GAS NF with and without treatment with an antibiotic, clindamycin (CLN). Methods Mice expressing the human HLA-II DR3 (DR3) or the HLA-II DR4 (DR4) allele were divided into three groups: i) uninfected controls, ii) subcutaneously infected with a clinical GAS strain isolated from a patient with GAS NF, and iii) GAS infected with CLN treatment (10mg/kg/5 days, intraperitoneal). The groups were monitored for 15 days post-infection. Skin GAS burden and lesion area, splenic and hippocampal mRNA levels of inflammatory markers, and immunohistochemical changes in hippocampal GFAP and Iba-1 immunoreactivity were assessed. Results Skin GAS burden and hippocampal mRNA levels of inflammatory markers S100A8/A9, IL-1β, IL-33, inflammasome-related caspase-1 (Casp1), and NLRP6 were elevated in infected DR3 but not DR4 mice. The levels of these markers were significantly reduced following CLN treatment in DR3 mice. Although GAS was not detectable in the brain, astrocyte and microglia activation were evident from increased GFAP and Iba-1 mRNA levels respectively, in DR3 and DR4 mice. However, CLN treatment significantly reduced GFAP immunoreactivity in DR3 mice and not DR4 mice. Conclusion Our data suggest a skin-brain axis during GAS NF demonstrating that peripherally induced pathological conditions regulate neuroimmune and gliotic events, and CLN may attenuate peripheral infection and subsequent neuroimmune changes in an HLA-II-dependent manner. ### Competing Interest Statement The authors have declared no competing interest.