Abstract
Influenza A virus is a major global pathogen of humans, and there is an unmet need for effective antivirals. Current antivirals against influenza A virus directly target the virus and are vulnerable to mutational resistance. Harnessing an effective host antiviral response is an attractive alternative. We show that brief exposure to low, non-toxic doses of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, promptly elicits an extended antiviral state that dramatically blocks influenza A virus production. Crucially, oral administration of TG protected mice against lethal virus infection and reduced virus titres in the lungs of treated mice. TG-induced ER stress unfolded protein response appears as a key driver responsible for activating a spectrum of host antiviral defences that include an enhanced type I/III interferon response. Our findings suggest that TG is potentially a viable host-centric antiviral for the treatment of influenza A virus infection without the inherent problem of drug resistance.
Highlights
There is no entirely satisfactory antiviral treatment for influenza A infections
We show that TG-induced endoplasmic reticulum (ER) stress leading to UPR is a key innate immune driver that mediates a range host-centric antiviral processes to block virus replication
As proof of principle for the antiviral use of TG in vivo, we examined its effects in mice subjected to lethal Puerto Rico/8/1934 H1N1 (PR8) H1N1 virus challenge
Summary
By directly targeting the highly mutable virus, current and near-market antivirals are inherently susceptible to virus resistance [1,2]. There is an unmet need for antivirals to be clinically effective and less vulnerable to viral mutation. An alternative antiviral approach is to target host factors that facilitate virus replication or promote host immune response [3,4]. Two distinct advantages underpin host-dependent therapies: they (i) do not directly target the virus proteins, thereby reducing selection pressure and the likelihood of drug resistant escape mutants and (ii) can target host factors shared by different viruses [5,6,7]. Harnessing an effective host antiviral response is potentially a better alternative or even a replacement for existing antivirals
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