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Thapsigargin inhibition of coronavirus PHEV replication by Ca2+ mediated metabolic reprogramming

ABSTRACT: The coronaviruses (CoVs) represent a large family of human and animal pathogens that cause significant health and economic burdens worldwide. Porcine hemagglutinating encephalomyelitis virus (PHEV), belonging to the genus Betacoronavirus, is one of the six coronaviruses that infect pigs, for which no effective drug or vaccine is commercially available. Here, we found that thapsigargin (Tg), an ER stress inducer, potently blocks PHEV replication in non-cytotoxic levels and the antiviral effect is long-lasting at least 60 h post-Tg exposure in different cells. Time-of-addition assay demonstrated that Tg significantly inhibit PHEV replication in N2a cells when treated immediately before, during, or after virus infection. Tg does not directly interact with PHEV particles and transcriptome analysis reveals a unique antiviral mechanism of Tg through Ca2+ mediated metabolic reprogramming. Crucially, oral administration of Tg prolong the survival time and reduced virus titres in the brains of treated mice. Besides, Tg also exerts a profound antiviral effect on alphacoronavirus, deltacoronavirus, rhabdoviruses, parapoxvirus and picornavirus. Taken together, Tg exerts antiviral effects by targeting host factors shared by different viruses, suggesting that this compound (or derivatives thereof) may be developed into broad-spectrum antiviral drugs without considering the drug resistance caused by virus mutation.

ORGANISM(S): Mus musculus

PROVIDER: GSE246447 | GEO | 2023/11/10

REPOSITORIES: GEO

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Project description:The major inducible 70 kDa heat shock protein (hsp70) is host protective in a mouse model of measles virus (MeV) brain infection. Transgenic constitutive expression of hsp70 in neurons, the primary target of MeV infection, abrogates neurovirulence in neonatal H-2d congenic C57BL/6 mice. A significant level of protection is retained after depletion of T lymphocytes, implicating innate immune mechanisms. Focus of the present work was to elucidate the basis for hsp70-dependent innate immunity using this model. Transcriptome analysis of brains from transgenic (TG) and non-transgenic (NT) mice 5 days after infection identified type 1 interferon (IFN) signaling and macrophage activation/antigen presentation as the main differences linked to survival. The pivotal role for type 1 IFN in hsp70-mediated protection was demonstrated in mice with a genetically disrupted type 1 IFN receptor (IFNAR-/-), where IFNAR-/- eliminated the difference in survival between TG and NT mice. Brain macrophages, not neurons, are the predominant source of type 1 IFN in the virus-infected brain, and in vitro studies provided a mechanistic basis by which MeV-infected neurons can induce IFN-β in uninfected microglia in an hsp70-dependent manner. MeV infection induced extracellular release of hsp70 from mouse neuronal cells that constitutively express hsp70, and extracellular hsp70 induced IFN-β transcription in mouse microglial cells through Toll-like receptors 2 and 4. Collectively, results support a novel axis of type 1 IFN-dependent antiviral immunity in the virus-infected brain that is driven by hsp70. Hsp70 expression in mice enhances gene expression related to antiviral immune response against MeV neurovirulence. We performed microarrays on whole brain tissues in mice to obtain an unbiased picture of how hsp70 alters host innate responses to viral infection. Hsp70-overexpressing transgenic (TG) and non-transgenic (NT) mice were infected with MeV intracranially, and total brain mRNA harvested at 5 and 10 days post infection (d.p.i.) was analyzed, sampling the hemisphere opposite the side of viral inoculation. Analysis includes 6 groups: infected TG at 5 d.p.i. (n=4), infected TG at 10 d.p.i. (n=5), infected NT at 5 d.p.i. (n=4), infected NT at 10 d.p.i. (n=5), uninfected TG at 5 d.p.i. (n=4), and uninfected NT at 5 d.p.i. (n=4).

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Thapsigargin inhibition of coronavirus PHEV replication by Ca2+ mediated metabolic reprogramming

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