Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality worldwide and is a frequent cause of skin and soft tissue infections (SSTIs). Lymphedema—fluid accumulation in tissue caused by impaired lymphatic vessel function—is a strong risk factor for SSTIs. SSTIs also frequently recur in patients and sometimes lead to acquired lymphedema. However, the mechanism of how SSTIs can be both the consequence and the cause of lymphatic vessel dysfunction is not known. Intravital imaging in mice revealed an acute reduction in both lymphatic vessel contractility and lymph flow after localized MRSA infection. Moreover, chronic lymphatic impairment is observed long after MRSA is cleared and inflammation is resolved. Associated with decreased collecting lymphatic vessel function was the loss and disorganization of lymphatic muscle cells (LMCs), which are critical for lymphatic contraction. In vitro, incubation with MRSA-conditioned supernatant led to LMC death. Proteomic analysis identified several accessory gene regulator (agr)–controlled MRSA exotoxins that contribute to LMC death. Infection with agr mutant MRSA resulted in sustained lymphatic function compared to animals infected with wild-type MRSA. Our findings suggest that agr is a promising target to preserve lymphatic vessel function and promote immunity during SSTIs.

耐甲氧西林金黄色葡萄球菌（MRSA）是全球发病率和死亡率的主要原因，并且是皮肤和软组织感染（SSTI）的常见原因。淋巴水肿是由淋巴管功能受损引起的组织中的液体积聚，是SSTI的重要危险因素。SSTI在患者中也经常复发，有时会导致获得性淋巴水肿。但是，尚不清楚SSTI如何成为淋巴管功能障碍的结果和原因的机制。小鼠的活体成像显示，局部MRSA感染后，淋巴管收缩力和淋巴流量均急剧降低。此外，在清除MRSA并消除炎症后很长时间即可观察到慢性淋巴损伤。与收集淋巴管功能降低相关的是淋巴肌细胞（LMC）的丢失和紊乱，这对于淋巴收缩至关重要。在体外，与MRSA条件的上清液一起孵育会导致LMC死亡。蛋白质组学分析确定了几种辅助基因调节剂（agr）控制的MRSA外毒素，导致LMC死亡。与野生型MRSA感染的动物相比，用agr突变型MRSA感染导致持续的淋巴功能。我们的发现表明，agr是在SSTI期间保留淋巴管功能并增强免疫力的有希望的靶标。