Induction of cyclophilin A by influenza A virus infection facilitates group A Streptococcus coinfection

Xiaoyuan Bai; Wenxian Yang; Xiaohan Luan; Huizi Li; Heqiao Li; Deyu Tian; Wenhui Fan; Jing Li; Beinan Wang; Wenjun Liu; Lei Sun

doi:10.1016/j.celrep.2021.109159

Induction of cyclophilin A by influenza A virus infection facilitates group A Streptococcus coinfection

Cell Rep. 2021 May 18;35(7):109159. doi: 10.1016/j.celrep.2021.109159.

Authors

Xiaoyuan Bai¹, Wenxian Yang¹, Xiaohan Luan¹, Huizi Li¹, Heqiao Li¹, Deyu Tian², Wenhui Fan², Jing Li¹, Beinan Wang¹, Wenjun Liu³, Lei Sun⁴

Affiliations

¹ 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.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
³ 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; Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Beijing 100101, China; Institute of Infectious Diseases, Shenzhen Bay Laboratory, Guangdong 518107, China. Electronic address: liuwj@im.ac.cn.
⁴ 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. Electronic address: sunlei362@im.ac.cn.

PMID: 34010655
DOI: 10.1016/j.celrep.2021.109159

Abstract

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.

Keywords: coinfection; cyclophilin A; group A Streptococcus; influenza A virus; secondary bacterial infection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Coinfection / microbiology*
Cyclophilin A / metabolism*
Humans
Influenza A virus / pathogenicity*
Streptococcus pneumoniae / virology*

Substances

Cyclophilin A