Abstract
ABSTRACTHuman respiratory syncytial virus (hRSV) is the most common pathogen which causes acute lower respiratory infection (ALRI) in infants. Recently, virus-host interaction has become a hot spot of virus-related research, and it needs to be further elaborated for RSV infection. In this study, we found that RSV infection significantly increased the expression of cyclophilin A (cypA) in clinical patients, mice, and epithelial cells. Therefore, we evaluated the function of cypA in RSV replication and demonstrated that virus proliferation was accelerated in cypA knockdown host cells but restrained in cypA-overexpressing host cells. Furthermore, we proved that cypA limited RSV replication depending on its PPIase activity. Moreover, we performed liquid chromatography-mass spectrometry, and the results showed that cypA could interact with several viral proteins, such as RSV-N, RSV-P, and RSV-M2-1. Finally, the interaction between cypA and RSV-N was certified by coimmunoprecipitation and immunofluorescence. Those results provided strong evidence that cypA may play an inhibitory role in RSV replication through interaction with RSV-N via its PPIase activity.IMPORTANCE RSV-N, packed in the viral genome to form the ribonucleoprotein (RNP) complex, which is recognized by the RSV RNA-dependent RNA polymerase (RdRp) complex to initiate viral replication and transcription, plays an indispensable role in the viral biosynthesis process. cypA, binding to RSV-N, may impair this function by weakening the interaction between RSV-N and RSV-P, thus leading to decreased viral production. Our research provides novel insight into cypA antiviral function, including binding to viral capsid protein to inhibit viral replication, which may be helpful for new antiviral drug exploration.
Highlights
Human respiratory syncytial virus is the most common pathogen which causes acute lower respiratory infection (ALRI) in infants
Researchers have found that cyclophilin A (cypA) could affect the replication of a variety of viruses, including DNA viruses such as hepatitis B virus (HBV) [31], human cytomegalovirus (HCMV) [32, 33], and Epstein-Barr virus (EBV) [13] and RNA viruses such as human immunodeficiency virus type 1 (HIV-1) [34,35,36,37,38] and flaviviruses [39]
We found that after RSV infection, the expression of cypA was significantly increased in clinical RSV infectious patients, RSV-infected mice and Hep2 cells
Summary
Human respiratory syncytial virus (hRSV) is the most common pathogen which causes acute lower respiratory infection (ALRI) in infants. The interaction between cypA and RSV-N was certified by coimmunoprecipitation and immunofluorescence Those results provided strong evidence that cypA may play an inhibitory role in RSV replication through interaction with RSV-N via its PPIase activity. Human respiratory syncytial virus (hRSV), which is related to about 22% of severe acute lower respiratory tract infections (ALRTI) worldwide [1], mainly infects children under 5 years old, the elderly, and persons who use immunosuppressive agents [2]. CypA could combine with Pr55gag, the Gag polyprotein of human immunodeficiency virus type 1 (HIV-1), through its PPIase activity to promote viral replication [8, 9]; PPIase activity of cypA inhibitors such as CSA, Debio 025, and NIM811 could block the interaction of cypA and hepatitis C virus (HCV) NS5A/5B protein complex, inhibiting viral replication [10]. In view of the role of cypA in the replication of many viruses [18], cypA can be used as a potential target to treat viral infections
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