Abstract
Our previous studies indicate that Cyclophilin A (CypA) impairs the replication of influenza A virus in vitro. To further evaluate the antiviral functions of CypA and explore its mechanism, transgenic mice with overexpression of CypA by two specific promoters with SPC (CypA-SPC) or CMV (CypA-CMV) were developed. After challenge with the A/WSN/33(H1N1) influenza virus, CypA-SPC and CypA-CMV transgenic mice displayed nearly 2.5- and 3.8-fold stronger disease resistance to virus infection, respectively, compared to wild-type animals. Virus replication, pathological lesions and inflammatory cytokines were substantially reduced in both lines of transgenic mice. In addition, after infection there was an upregulation of genes associated with cell migration, immune function, and organ development; and a downregulation of genes associated with the positive regulation of immune cells and apoptosis in the peritoneal macrophages of CypA-overexpressing transgenic mice (CypA+). These results indicate that CypA is a key modulator of influenza virus resistance in mice, and that CypA+ mice constitutes an important model to study the roles of CypA in the regulation of immune responses and infections.
Highlights
Our previous studies indicate that Cyclophilin A (CypA) impairs the replication of influenza A virus in vitro
We found that CypA inhibits influenza virus replication in vitro[22,35,36]
The founders of the CypA-overexpressing transgenic mice (CypA+)mouse lines were confirmed for CypA expression at the protein and the nucleic acid levels, with greater than twice the expression levels of CypA in the lungs compared to wild type mice (Fig. 1A,B), and possessing the specific promoter for CypA expression in tail tissues (Fig. 1C,D)
Summary
Our previous studies indicate that Cyclophilin A (CypA) impairs the replication of influenza A virus in vitro. After infection there was an upregulation of genes associated with cell migration, immune function, and organ development; and a downregulation of genes associated with the positive regulation of immune cells and apoptosis in the peritoneal macrophages of CypA-overexpressing transgenic mice (CypA+) These results indicate that CypA is a key modulator of influenza virus resistance in mice, and that CypA+ mice constitutes an important model to study the roles of CypA in the regulation of immune responses and infections. T-cell activation is blocked in the presence of the CsA-CypA complex, resulting in the reduced expression of pro-inflammatory cytokines and an overall decrease in the immune response[8]. Cytokine responses and an analysis of transcriptomes from the peritoneal macrophages of infected mice are presented
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