(Correspondent He Ruirui) on April 20, Nature Communications published the latest research news from Professor Wang Chenhui's group, School of Life Science, Huazhong University of Science and Technology: "TAGAP instruments Th17 differentiation by bringing decision activation to EphB2 signaling in native antifungal response".

Fungal infection is one of the main causes of death in patients with cancer, AIDS and compromised immunity. At present, the number of deaths caused by fungal infection in the world reaches 1.5 million every year, which is equivalent to the deaths caused by AIDS and tuberculosis. In 2019, the mortality rate of ear fungal infection reached 60%, which greatly threatened people's life and health. Fungal infection has become one of the major public health crises in the world. Among the fungal infections, Candida albicans infection is the most common, which is one of the main strains leading to nosocomial infection! At present, due to the insufficient research in antifungal immune signal pathway, relatively few antifungal drugs and the emergence of drug-resistant fungi strains, the control of fungal infection in the world is facing a huge challenge.

Many of genetic studies have found that the polymorphism of human TAGAP gene is related to the susceptibility of candidemia (the polymorphism of rs3127214 locus of TAGAP is closely related to the susceptibility of candidemia (the mortality rate is up to 40% - 75%), suggesting that TAGAP may participate in the antifungal immune signaling pathway. However, the specific role and mechanism of TAGAP in antifungal immunity are not very clear; in addition, the polymorphisms of TAGAP were identified to lead to the increased susceptibility to a variety of autoimmune diseases, including multiple sclerosis and inflammatory bowel disease, while the internal mechanism is unclear. In order to study the functional role of TAGAP in antifungal immunity, we studied the mechanism of TAGAP through cell level, TAGAP knockout mouse level and the human peripheral blood mononuclear cells (PBMCs) which carries the TAGAP rs3127214 polymorphism.

In this study, author first found that Dectin-1, dectin-2 / 3 and mincle ligands-mediated signaling pathway activation had defect in TAGAP-deficient macrophages, which confirmed that TAGAP played an important role in antifungal immunity. Through further molecular mechanism study, author found that in the antifungal immune signaling pathway induced by Dectin-1 / 2 / 3 ligand, the upstream molecule Syk phosphorylated receptor tyrosine kinase EphB2. Subsequently, the activated EphB2 further phosphorylated the 310th tyrosine site of TAGAP. Phosphorylated TAGAP recruits downstream signal molecule CARD9 to activate NF-κB/MAPK signaling pathways, and mediates the expression of proinflammatory cytokines such as IL-2, IL-6, IL-12 and IL-23. Specific proinflammatory cytokines such as IL-23 and IL-6 promote T cells to differentiate into Th17 cells and mediate fungal clearance. TAGAP deficiency or decreased expression Oof human TAGAP due to gene variation lead to abnormal activation of antifungal signaling pathway and decrease of cytokine secretion, which leads to abnormal differentiation of Th17 cells in vivo and increase susceptibility to candidemia (Fig. 1). In addition, we also found that compared with wild-type control mice, TAGAP-deficient mice had faster weight loss and higher mortality rate caused by Candida albicans infection, which further confirmed the important role of TAGAP in antifungal immunity. This study proves that TAGAP plays an important role in antifungal immunity and Th17 cell differentiation, which provides clues for the further understanding of antifungal immunity.

As it was known that Th17 cells also play an important role in the pathogenesis of autoimmune diseases, such as multiple sclerosis, and we found that EPHB2-TAGAP-CARD9 signal axis is very important for the differentiation of Th17 cells in vivo. Therefore, we also explored whether the kinase inhibitor of EphB2 has any therapeutic effect on experimental encephalomyelitis (mouse model of human multiple sclerosis). Interestingly, We found that these two EPHB2 inhibitors, dasatinib and vandetanib (both are FDA proved drugs), can inhibit the differentiation of Th17 cells in vivo and the severity of experimental encephalomyelitis in mice (vandetanib has better therapeutic effect than dasatinib), which suggests that these two drugs may have the potential therapeutic effect on human multiple sclerosis. This study not only clarifies the molecular mechanism and functional role of TAGAP in antifungal immunity, but also explores the mechanism of the susceptibility of autoimmune diseases caused by abnormality of antifungal immunity, and provides a target for the treatment of autoimmune diseases such as multiple sclerosis.

Fig 1. Molecular mechanism model of TAGAP involved in anti-fungal immune signaling pathway

Professor Chenhui Wang, Professor Zhang Cunjin and Dr. Wanwei Sun are the co-correspondence authors of the paper. Dr. Chen Jianwen and He Ruirui are the co-first authors of the paper. This work was supported by the general program of NSFC (fund No. 2017050304010294) and Wuhan Chenguang program (fund No. 81871280).

Article link: https://www.nature.com/articles/s41467-020-15564-7