State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518000, China.
Cell Chem Biol. 2017 Feb 16;24(2):182-194. doi: 10.1016/j.chembiol.2016.12.014. Epub 2017 Jan 19.
Talaromyces (Penicillium) marneffei is one of the leading causes of systemic mycosis in immunosuppressed or AIDS patients in Southeast Asia. How this intracellular pathogen evades the host immune defense remains unclear. We provide evidence that T. marneffei depletes levels of a key proinflammatory lipid mediator arachidonic acid (AA) to evade the host innate immune defense. Mechanistically, an abundant secretory mannoprotein Mp1p, shown previously to be a virulence factor, does so by binding AA with high affinity via a long hydrophobic central cavity found in the LBD2 domain. This sequesters a critical proinflammatory signaling lipid, and we see evidence that AA, AA's downstream metabolites, and the cytokines interleukin-6 and tumor necrosis factor α are downregulated in T. marneffei-infected J774 macrophages. Given that Mp1p-LBD2 homologs are identified in other fungal pathogens, we expect that this novel class of fatty-acid-binding proteins sequestering key proinflammatory lipid mediators represents a general virulence mechanism of pathogenic fungi.
马尔尼菲青霉是东南亚地区免疫抑制或艾滋病患者系统性真菌感染的主要病原体之一。这种细胞内病原体如何逃避宿主免疫防御仍不清楚。我们提供的证据表明，马尔尼菲青霉消耗关键促炎脂质介质花生四烯酸 (AA) 的水平，以逃避宿主先天免疫防御。从机制上讲，先前被证明是毒力因子的丰富分泌甘露糖蛋白 Mp1p 通过其在 LBD2 结构域中发现的长疏水性中央腔与 AA 高亲和力结合来实现这一点。这就隔离了一种关键的促炎信号脂质，我们有证据表明，在感染马尔尼菲青霉的 J774 巨噬细胞中，AA、AA 的下游代谢物以及细胞因子白细胞介素-6 和肿瘤坏死因子-α 下调。鉴于其他真菌病原体中鉴定出了 Mp1p-LBD2 同源物，我们预计这种新型脂肪酸结合蛋白隔离关键促炎脂质介质代表了致病真菌的一般毒力机制。
