Abstract
Influenza A virus infection is usually associated with acute lung injury, which is typically characterized by tracheal mucosal barrier damage and an interleukin 17A (IL-17A)-mediated inflammatory response in lung tissues. Although targeting IL-17A has been proven to be beneficial for attenuating inflammation around lung cells, it still has a limited effect on pulmonary tissue recovery after influenza A virus infection. In this research, interleukin 22 (IL-22), a cytokine involved in the repair of the pulmonary mucosal barrier, was fused to the C-terminus of the anti-IL-17A antibody vunakizumab to endow the antibody with a tissue recovery function. The vunakizumab-IL22 (vmab-IL-22) fusion protein exhibits favorable stability and retains the biological activities of both the anti-IL-17A antibody and IL-22 in vitro. Mice infected with lethal H1N1 influenza A virus and treated with vmab-mIL22 showed attenuation of lung index scores and edema when compared to those of mice treated with saline or vmab or mIL22 alone. Our results also illustrate that vmab-mIL22 triggers the upregulation of MUC2 and ZO1, as well as the modulation of cytokines such as IL-1β, HMGB1 and IL-10, indicating the recovery of pulmonary goblet cells and the suppression of excessive inflammation in mice after influenza A virus infection. Moreover, transcriptome profiling analysis suggest the downregulation of fibrosis-related genes and signaling pathways, including genes related to focal adhesion, the inflammatory response pathway, the TGF-β signaling pathway and lung fibrosis upon vmab-mIL22 treatment, which indicates that the probable mechanism of vmab-mIL22 in ameliorating H1N1 influenza A-induced lung injury. Our results reveal that the bifunctional fusion protein vmab-mIL22 can trigger potent therapeutic effects in H1N1-infected mice by enhancing lung tissue recovery and inhibiting pulmonary inflammation, which highlights a potential approach for treating influenza A virus infection by targeting IL-17A and IL-22 simultaneously.
Highlights
H1N1 influenza A virus, one of the major subtypes disseminated in humans, has been reported to cause acute respiratory illness such as acute lung injury, especially in patients with severe form
Interleukin 17A (IL-17A) is associated with exacerbated influenza-associated pathology [6, 49]
Accumulated experimental and clinical evidence has broadened our understanding of the role of IL-17A in influenza virus infections and suggests that IL-17A-targeted immunotherapy may be a promising therapeutic option, whereas positive data on the therapeutic effect of antibodies targeting IL-17A on lung injury caused by influenza virus are still limited
Summary
H1N1 influenza A virus, one of the major subtypes disseminated in humans, has been reported to cause acute respiratory illness such as acute lung injury, especially in patients with severe form. Lung function impairment caused by an excessive inflammatory response was reported to be the main cause of the deaths [1,2,3,4]. Recent studies showed that IL-17A was overexpressed in lung tissues after mice were infected with influenza A/PR/8 for 2 days, which caused the excessive recruitment and accumulation of inflammatory cells and serious lung injury [11]. Knockout of IL-17A gene could impair the production of IL-1b, IL-23 and TNF-a, which remarkably rescued pulmonary function and increased survival in virus-infected mice by attenuating inflammation, indicating that targeting IL-17A might be a potential approach for ameliorating the abnormal immune response during virus-induced lung injury [8, 12, 13]. The blockade of IL-17A signaling alleviates tissue damage and inflammation during virus infection in murine models, targeting IL-17A alone has limited efficacy in repairing the tissue damage caused by influenza A virus infection [14]
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