Induction of cyclophilin A by influenza A virus infection facilitates group A Streptococcus coinfection
Induction of cyclophilin A by influenza A virus infection facilitates group A Streptococcus coinfection
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DOI：
10.1016/j.celrep.2021.109159
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发表时间：
2021-05-18
期刊：
影响因子：
8.8
通讯作者：
Sun, Lei
中科院分区：
文献类型：
--
作者：
Bai, Xiaoyuan;Yang, Wenxian;Sun, Lei
在甲型流感流行期间，细菌合并感染是发病率和死亡率增加的主要原因。然而，宿主因子在调节甲型流感病毒（IAV）触发的细菌共感染中的作用仍然是难以捉摸的。亲环素A（Cyclophilin A，CypA）是一种重要的感染和免疫调节因子。在这里，我们表明，IAV诱导的CypA表达促进A组链球菌（GAS）在体外和体内的共感染。在IAV感染后，CypA与粘着斑激酶（FAK）相互作用并抑制E3连接酶cCbl介导的、K48连接的FAK泛素化，其通过FAK/Akt信号传导途径正向调节整合素α 5表达和肌动蛋白重排以促进GAS定殖和侵袭。值得注意的是，CypA缺陷或环孢菌素A的抑制显著抑制小鼠中IAV触发的GAS共感染。综上所述，CypA在GAS感染中起重要作用，而CypA的诱导表达是IAV促进细菌共感染的另一途径，提示CypA是继发性细菌感染的一个有希望的治疗靶点。
During influenza A epidemics, bacterial coinfection is a major cause of increased morbidity and mortality. However, the roles of host factors in regulating influenza A virus (IAV)-triggered bacterial coinfection remain elusive. Cyclophilin A (CypA) is an important regulator of infection and immunity. Here, we show that IAV-induced CypA expression facilitates group A Streptococcus (GAS) coinfection both in vitro and in vivo. Upon IAV infection, CypA interacts with focal adhesion kinase (FAK) and inhibited E3 ligase cCbl-mediated, K48-linked ubiquitination of FAK, which positively regulates integrin alpha 5 expression and actin rearrangement via the FAK/Akt signaling pathway to facilitate GAS colonization and invasion. Notably, CypA deficiency or inhibition by cyclosporine A significantly inhibits IAV-triggered GAS coinfection in mice. Collectively, these findings reveal that CypA is critical for GAS infection, and induction of CypA expression is another way for IAV to promote bacterial coinfection, suggesting that CypA is a promising therapeutic target for the secondary bacterial infection.