Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Cell Host Microbe. 2017 Nov 8;22(5):678-687.e9. doi: 10.1016/j.chom.2017.09.004. Epub 2017 Oct 19.
The virulence factors of pathogenic microbes often have single functions that permit immune suppression. However, a proportion possess multiple activities and are considered moonlighting proteins. By examining secreted virulence factors of Staphylococcus aureus, we determine that the bacterial lipoic acid synthetase LipA suppresses macrophage activation. LipA is known to modify the E2 subunit of the metabolic enzyme complex pyruvate dehydrogenase (E2-PDH) with a fatty acid derivative, lipoic acid, yielding the metabolic protein lipoyl-E2-PDH. We demonstrate that lipoyl-E2-PDH is also released by S. aureus and moonlights as a macrophage immunosuppressant by reducing Toll-like receptor 1/2 (TLR1/2) activation by bacterial lipopeptides. A LipA-deficient strain induces heightened pro-inflammatory cytokine production, which is diminished in the absence of TLR2. During murine systemic infection, LipA suppresses pro-inflammatory macrophage activation, rendering these cells inefficient at controlling infection. These observations suggest that bacterial metabolism and immune evasion are linked by virtue of this moonlighting protein.
致病微生物的毒力因子通常具有单一的功能，可实现免疫抑制。然而，有一部分毒力因子具有多种活性，被认为是具有双重功能的蛋白。通过研究金黄色葡萄球菌分泌的毒力因子，我们发现细菌硫辛酸合酶 LipA 可抑制巨噬细胞的激活。已知 LipA 用脂肪酸衍生物硫辛酸修饰代谢酶复合物丙酮酸脱氢酶（E2-PDH）的 E2 亚基，生成代谢蛋白脂酰-E2-PDH。我们证明脂酰-E2-PDH 也可由金黄色葡萄球菌释放，并通过降低细菌脂肽对 Toll 样受体 1/2（TLR1/2）的激活，充当巨噬细胞免疫抑制剂。LipA 缺失株可诱导产生更高水平的促炎细胞因子，而 TLR2 缺失则可降低该水平。在小鼠全身感染期间，LipA 抑制促炎巨噬细胞的激活，使这些细胞不能有效控制感染。这些观察结果表明，细菌代谢与免疫逃避通过这种双重功能蛋白而联系在一起。
