Talaromyces marneffei promotes M2-like polarization of human macrophages by downregulating SOCS3 expression and activating the TLR9 pathway

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.

Talaromyces marneffei Infection: Virulence, Intracellular Lifestyle and Host Defense Mechanisms

“…Moreover, the inhibiting effect against M1 polarization has also been reported in T. marneffei infected THP-1 human macrophages by disturbances CD86 (B7-2) expression [123]. The studies by Wei et al (2021) demonstrated that SOCS3-STAT6 intracellular signaling components and the TLR9 signaling pathways directly participated in macrophage M2-like polarization and these investigators hypothesized that T. marneffei may escape macrophage killing to proliferate inside macrophage by inducing M2-like polarization [124]. The cytokine signaling pathway in T. marneffei infected human macrophage have been investigated.…”

Overexpression of CD86 enhances the ability of THP‐1 macrophages to defend against Talaromyces marneffei

“…Research studies have pointed out that T. marneffei avoids macrophage killing by modulating the SOCS3‐STAT6 and the TLR9 pathways to induce M2‐like polarization in human THP‐1 macrophages. 15 Some findings suggest that IL‐6 expression is downregulated during T. marneffei infection in bronchial epithelial cells, which may promote T. marneffei invasion. 16 We speculated that T. marneffei may adsorb or uptake CD86 in the supernatant produced by macrophages when facing THP‐1 cells to resist the antifungal mechanisms of macrophages.…”

Key thermally dimorphic fungal pathogens: shaping host immunity

“…Here, the authors showed that by inhibiting TLR9 activation, this response was partially blocked. This study suggests that the antifungal ability of macrophages depends on their activation status [ 87 ].…”