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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

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Stimulation of alpha2-adrenergic receptors impairs influenza virus infection.

Matsui Ken K Ozawa Makoto M Kiso Maki M Yamashita Makoto M Maekawa Toshihiko T Kubota Minoru M Sugano Sumio S Kawaoka Yoshihiro Y

Scientific reports 20180315 1

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 ...[more]

PMID: 29545586

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Project description:Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral ?2- and ?3-adrenergic receptors (?2- and ?3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor ? (TNF?), interleukin-1? (IL-1?), and interleukin-6 (IL-6). Here, we first sought to investigate the role of ?2- and ?3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15?mg/kg/day) or vehicle for 14?days. The ?2AR antagonist ICI118551 and ?3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNF? inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35?days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3?weeks after OR486 cessation. Corresponding increases in spinal TNF?, IL-1?, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral ?2- and ?3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.

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Stimulation of alpha2-adrenergic receptors impairs influenza virus infection.

Publications

Stimulation of alpha2-adrenergic receptors impairs influenza virus infection.

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