ABSTRACT

Little is known about how Talaromyces marneffei, a thermally dimorphic fungus that causes substantial morbidity and mortality in Southeast Asia, evades the human immune system. Polarization of macrophages into fungal-inhibiting M1-like and fungal-promoting M2-like types has been shown to play an important role in the innate immune response against fungal pathogens. This mechanism has not been defined for T. marneffei. Here, we demonstrated that T. marneffei promotes its survival in human macrophages by inducing them toward M2-like polarization. Our investigations of the mechanism revealed that T. marneffei infection led to SOCS3 protein degradation by inducing tyrosine phosphorylation, thereby relieving the inhibitory effect of SOCS3 on p-STAT6, a key factor for M2-like polarization. Our SOCS3-overexpression experiments showed that SOCS3 is a positive regulator of M1-like polarization and plays an important role in limiting M2-like polarization. Furthermore, we found that inhibition of the TLR9 pathway partially blocked T. marneffei-induced M2-like polarization and significantly enhanced the killing activity of macrophages against T. marneffei. Collectively, these results reveal a novel mechanism by which T. marneffei evades the immune response of human macrophages.

摘要

很少有人知道Talaromyces marneffei是一种在东南亚造成大量发病率和死亡率的热二态真菌，它是如何逃避人类免疫系统的。巨噬细胞极化为抑制真菌的 M1 样和促进真菌的 M2 样类型已被证明在针对真菌病原体的先天免疫反应中发挥重要作用。尚未为T. marneffei定义此机制。在这里，我们证明了T. marneffei通过诱导人类巨噬细胞走向 M2 样极化来促进其在人类巨噬细胞中的存活。我们对该机制的研究表明，T. marneffei感染通过诱导酪氨酸磷酸化导致 SOCS3 蛋白降解，从而减轻 SOCS3 对 p-STAT6 的抑制作用，p-STAT6 是 M2 样极化的关键因素。我们的 SOCS3 过表达实验表明，SOCS3 是 M1 样极化的正调节剂，在限制 M2 样极化中起重要作用。此外，我们发现 TLR9 通路的抑制部分阻断了T. marneffei诱导的 M2 样极化，并显着增强了巨噬细胞对T. marneffei的杀伤活性。总的来说，这些结果揭示了一种新的机制，通过该机制，T. marneffei逃避了人类巨噬细胞的免疫反应。