Stimulation of alpha2-adrenergic receptors impairs influenza virus infection.

ABSTRACT: Influenza A viruses cause seasonal epidemics and occasional pandemics. The emergence of viruses resistant to neuraminidase (NA) inhibitors and M2 ion channel inhibitors underlines the need for alternate anti-influenza drugs with novel mechanisms of action. Here, we report the discovery of a host factor as a potential target of anti-influenza drugs. By using cell-based virus replication screening of a chemical library and several additional assays, we identified clonidine as a new anti-influenza agent in vitro. We found that clonidine, which is an agonist of the alpha2-adrenergic receptor (?2-AR), has an inhibitory effect on the replication of various influenza virus strains. ?2-AR is a Gi-type G protein-coupled receptor that reduces intracellular cyclic AMP (cAMP) levels. In-depth analysis showed that stimulation of ?2-ARs leads to impairment of influenza virus replication and that ?2-AR agonists inhibit the virus assembly step, likely via a cAMP-mediated pathway. Although clonidine administration did not reduce lung virus titers or prevent body weight loss, it did suppress lung edema and improve survival in a murine lethal infection model. Clonidine may thus protect against lung damage caused by influenza virus infection. Our results identify ?2-AR-mediated signaling as a key pathway to exploit in the development of anti-influenza agents.

SUBMITTER: Matsui K 

PROVIDER: S-EPMC5854622 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature