CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Cell Rep. 2021 May 18;35(7):109159. doi: 10.1016/j.celrep.2021.109159.
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 α5 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.
在甲型流感流行期间，细菌合并感染是导致发病率和死亡率增加的主要原因。然而，宿主因素在调节甲型流感病毒（IAV）引发的细菌合并感染中的作用仍不清楚。亲环素 A（CypA）是感染和免疫的重要调节剂。在这里，我们表明，IAV 诱导的 CypA 表达促进了体外和体内的 A 组链球菌（GAS）合并感染。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 FAK 的 K48 连接泛素化，这通过 FAK/Akt 信号通路正向调节整合素 α5 的表达和肌动蛋白重排，从而促进 GAS 的定植和侵袭。值得注意的是，CypA 缺陷或环孢素 A 的抑制显著抑制了小鼠中 IAV 引发的 GAS 合并感染。总之，这些发现表明 CypA 对 GAS 感染至关重要，并且 CypA 表达的诱导是 IAV 促进细菌合并感染的另一种方式，这表明 CypA 是继发性细菌感染的一个有前途的治疗靶点。
