Rago Flavia, Ahmed Mohamed Y, Marinelli Michael A, Miller Leigh M, Duray Alexis M, Dresden Brooke P, Constantinesco Nicholas J, Sims Peyton K F, Richwalls Lacee J, Kupul Saran, Kolls Jay K, Gopal Radha, Alcorn John F
Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States.
Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, United States.
J Immunol. 2025 Apr 1;214(4):703-713. doi: 10.1093/jimmun/vkae061.
Staphylococcus aureus is a commensal and opportunist pathogen of the upper respiratory tract. The recognition of pathogen-associated molecular patterns through pattern-recognition receptors is crucial for eliminating microorganisms such as S. aureus. DC-SIGN (CD209) is a pattern-recognition receptor that binds to a broad range of pathogens, promoting phagocytosis. Here we aimed to study the role of mouse homologues of DC-SIGN, CD209d/e, in a methicillin-resistant S. aureus (MRSA) pulmonary infection model. CD209d/e-/- and wild-type C57BL/6 mice were infected with MRSA and inflammatory parameters were evaluated. CD209d/e-/- mice had delayed bacterial burden and mortality together with increased frequency of neutrophils and decreased dendritic cells in the lung compared with control mice. iNOS+ macrophages, and regulatory T cell frequency were decreased in the lungs of CD209d/e-/- mice. CD209d/e-/- mice had increased levels of inflammatory cytokines in the lungs, but levels of IL-12p40 were decreased. MRSA reduced expression of interferon-γ and pattern-recognition receptors in CD209d/e-/- mice. MRSA uptake by phagocytes was decreased in the lungs of CD209d/e-/- versus control mice. CD209d/e-/- bone marrow derived macrophages showed impaired MRSA uptake and killing. These data suggest that CD209d/e are essential receptors to control inflammation by activating macrophages leading to MRSA uptake and killing.
金黄色葡萄球菌是上呼吸道的共生兼机会致病菌。通过模式识别受体识别病原体相关分子模式对于清除诸如金黄色葡萄球菌等微生物至关重要。DC-SIGN（CD209）是一种模式识别受体，可与多种病原体结合，促进吞噬作用。在此，我们旨在研究DC-SIGN的小鼠同源物CD209d/e在耐甲氧西林金黄色葡萄球菌（MRSA）肺部感染模型中的作用。将CD209d/e基因敲除小鼠和野生型C57BL/6小鼠感染MRSA，并评估炎症参数。与对照小鼠相比，CD209d/e基因敲除小鼠的细菌负荷和死亡率延迟，同时肺中中性粒细胞频率增加，树突状细胞减少。CD209d/e基因敲除小鼠肺中的诱导型一氧化氮合酶阳性巨噬细胞和调节性T细胞频率降低。CD209d/e基因敲除小鼠肺中的炎症细胞因子水平升高，但白细胞介素-12p40水平降低。MRSA降低了CD209d/e基因敲除小鼠中干扰素-γ和模式识别受体的表达。与对照小鼠相比，CD209d/e基因敲除小鼠肺中吞噬细胞对MRSA的摄取减少。CD209d/e基因敲除的骨髓来源巨噬细胞对MRSA的摄取和杀伤受损。这些数据表明，CD209d/e是通过激活巨噬细胞导致MRSA摄取和杀伤来控制炎症的必需受体。
