Epithelial Therapeutic Unit, National Institute of Allergy, and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2024 Sep 14;25(18):9933. doi: 10.3390/ijms25189933.
Infections caused by methicillin-resistant (MRSA) are a major public health burden. Emerging antibiotic resistance has heightened the need for new treatment approaches for MRSA infection such as developing novel antimicrobial agents and enhancing the host's defense response. The thermo-ion channels Transient Receptor Potential (TRP-) A1 and V1 have been identified as modulators of quorum sensing in cell culture models. However, their effects on in vivo infection control are unknown. In this study, we investigated the therapeutic effect of natural TRP ion channel inhibitors on MRSA skin infection in mice. While deletion of TRPV1 did not affect lesion size or inflammatory markers, TRPA1 mice demonstrated significantly reduced infection severity and abscess size. Treatment with natural inhibitors of TRPA1 with or without blockade of TRPV1 also reduced abscess size. Tissue transcriptomic data coupled with immunohistochemistry revealed that TRPA1 inhibition impacted heat shock protein expression (HSP), modulated the HIF-1a and MAPK pathways, and reduced IL4 expression. Additionally, metabolomics data showed an impact on purine and glycosaminoglycan pathways. Multi-omic integration of transcriptomic and metabolic data revealed that diacylglycerol metabolism was the likely bridge between metabolic and immunological impacts. Our findings suggest that TRPA1 antagonism could provide a promising and cost-effective therapeutic approach for reducing the severity of MRSA infection, and presents a novel underlying molecular mechanism.
耐甲氧西林金黄色葡萄球菌（MRSA）感染是一个主要的公共卫生负担。新兴的抗生素耐药性加剧了人们对治疗 MRSA 感染的新方法的需求，例如开发新型抗菌药物和增强宿主的防御反应。瞬时受体电位（TRP）-A1 和 V1 等热离子通道已被确定为细胞培养模型中群体感应的调节剂。然而，它们对体内感染控制的影响尚不清楚。在这项研究中，我们研究了天然 TRP 离子通道抑制剂对小鼠 MRSA 皮肤感染的治疗效果。虽然 TRPV1 的缺失并不影响病变大小或炎症标志物，但 TRPA1 小鼠表现出明显减轻的感染严重程度和脓肿大小。用天然的 TRPA1 抑制剂治疗，无论是否阻断 TRPV1，也能减小脓肿的大小。组织转录组数据加上免疫组织化学显示，TRPA1 抑制作用影响热休克蛋白表达（HSP），调节 HIF-1a 和 MAPK 途径，并减少 IL4 的表达。此外，代谢组学数据显示嘌呤和糖胺聚糖途径受到影响。转录组和代谢组数据的多组学整合表明，二酰基甘油代谢是代谢和免疫影响之间的可能桥梁。我们的研究结果表明，TRPA1 拮抗作用可能为减轻 MRSA 感染的严重程度提供一种有前途且具有成本效益的治疗方法，并提出了一种新的潜在分子机制。
