The antiviral effects of tankyrase inhibition on influenza A virus

Abstract

Influenza A virus is one of the most prevalent human pathogens, being a persistent global concern due to frequent mutations and formation of new virus strains. The influenza A virus infection may induce immune responses in the lungs leading to prolonged inflammation. In the worst-case influenza A infection may induce a cytokine storm and pulmonary fibrosis, which may be fatal. Several regulating pathways affect viral replication and pulmonary fibrosis, including the WNT/-catenin signaling and YAP signaling pathways, where the regulatory protein: tankyrase, play an important role. Controlling the WNT and YAP pathways may be a strategy for development of novel anti-viral drugs, treating both the viral infections and fibrosis. In the current study, we evaluated the effects of the highly potent and specific small-molecule tankyrase inhibitor OM-153 against influenza A replication, fibrosis development, cytokine response, and other immune functions. A C57BL/6 mice model was used to test whether OM-153 could counteract influenza A-induced body weight loss, lung damage, and fibrosis using two different influenza A strains: H1N1 and H5N1. In in vitro models, the influenza A virus strains H1N1, H5N1, and H7N1 were used. In the influenza A-infected mice, we found that OM-153 could counteract viral load and induced expression of inflammatory cytokines as well as markers for fibrosis, WNT, and YAP signaling. In cell culture, we found that OM-153 cannot counteract influenza A-reduced cell viability, nor induced expression of markers for fibrosis and WNT signaling. However, we show that OM-153 counteract viral load and induced expression of markers for YAP signaling. In addition, we found that the full-scale OM-153 treatment effect is dependent on CD4+ and CD8+ T-cells and B-cells. Further in vivo and in vitro experiments will be needed to deconvolute the mechanism behind the OM-153 anti-viral treatment effect. Our results demonstrate tankyrase inhibition as a potential treatment for influenza A virus infections and influenza A-induced lung damage.