Ambigapathy Ganesh, Mukundan Santhosh, Nagamoto-Combs Kumi, Combs Colin K, Nookala Suba
Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
Pathogens. 2023 Jul 31;12(8):1000. doi: 10.3390/pathogens12081000.
(Group A Streptococcus, GAS) bacteria cause a spectrum of human diseases ranging from self-limiting pharyngitis and mild, uncomplicated skin infections (impetigo, erysipelas, and 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). 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 (10 mg/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. Skin GAS burden and hippocampal mRNA levels of the 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 (GFAP) and microglia (Iba-1) activation were evident from increased GFAP and Iba-1 mRNA levels in DR3 and DR4 mice. However, CLN treatment significantly reduced GFAP mRNA levels in DR3 mice, not DR4 mice. Our data suggest a skin-brain axis during GAS NF, demonstrating that peripherally induced pathological conditions regulate neuroimmune changes and gliotic events in the brain.
A组链球菌（GAS）可引发一系列人类疾病，从自限性咽炎和轻度、无并发症的皮肤感染（脓疱病、丹毒和蜂窝织炎）到高度致病且迅速侵袭、危及生命的感染，如链球菌中毒性休克综合征和坏死性筋膜炎（NF）。HLA II类等位基因多态性与GAS感染的不同结局和严重程度相关。侵袭性GAS感染引发的免疫反应失调和外周细胞因子风暴增加了基因易感个体发生中毒性休克和多器官功能衰竭的风险。我们推测，虽然宿主免疫介质调节针对外周GAS感染的免疫反应，但这些相互作用可能同时引发神经病理学变化，在某些情况下，还会诱导神经胶质细胞表型的持续改变。在此，我们在有或没有用抗生素克林霉素（CLN）治疗的GAS NF的HLA-II转基因小鼠模型中，研究了外周GAS皮肤感染对大脑的影响。表达人类HLA-II DR3（DR3）或HLA-II DR4（DR4）等位基因的小鼠被分为三组：（i）未感染对照组，（ii）皮下注射从一名GAS NF患者分离的临床GAS菌株，（iii）GAS感染并用CLN治疗（10mg/kg/5天，腹腔注射）。感染后对各组进行15天的监测。评估皮肤GAS负荷和病变面积、脾脏和海马中炎症标志物的mRNA水平，以及海马中胶质纤维酸性蛋白（GFAP）和离子钙结合衔接分子1（Iba-1）免疫反应性的免疫组织化学变化。感染的DR3小鼠而非DR4小鼠的皮肤GAS负荷以及炎症标志物S100A8/A9、白细胞介素-1β（IL-1β）、白细胞介素-33（IL-33）、炎性小体相关半胱天冬酶-1（Casp1）和核苷酸结合寡聚化结构域样受体蛋白6（NLRP6）的海马mRNA水平升高。CLN治疗后，DR3小鼠中这些标志物的水平显著降低。尽管在大脑中未检测到GAS，但DR3和DR4小鼠中胶质纤维酸性蛋白（GFAP）和离子钙结合衔接分子1（Iba-1）的mRNA水平升高，表明星形胶质细胞（GFAP）和小胶质细胞（Iba-1）被激活。然而，CLN治疗显著降低了DR3小鼠而非DR4小鼠的GFAP mRNA水平。我们的数据表明在GAS NF期间存在皮肤-脑轴，表明外周诱导的病理状况调节大脑中的神经免疫变化和胶质细胞增生事件。
