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Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases.

ABSTRACT: Porcine epidemic diarrhea (PED) virus (PEDV) is a coronavirus that primarily infects porcine intestinal epithelial cells and causes severe diarrhea and high fatality in piglets. A77 1726 is the active metabolite of leflunomide, a clinically approved anti-rheumatoid arthritis (RA) drug. A77 1726 inhibits the activity of protein tyrosine kinases (PTKs), p70 S6 kinase (S6K1), and dihydroorotate dehydrogenase (DHO-DHase). Whether A77 1726 can control coronavirus infections has not been investigated. Here we report that A77 1726 effectively restricted PEDV replication by inhibiting Janus kinases (JAKs) and Src kinase activities but not by inhibiting DHO-DHase and S6K1 activities. Overexpression of Src, JAK2 or its substrate STAT3 enhanced PEDV replication and attenuated the antiviral activity of A77 1726. Our study demonstrates for the first time the ability of A77 1726 to control coronavirus replication by inhibiting PTK activities. Leflunomide has potential therapeutic value for the control of PEDV and other coronavirus infections.

SUBMITTER: Li X

PROVIDER: S-EPMC7301827 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases.

Li Xiaomei X Sun Jing J Prinz Richard A RA Liu Xiufan X Xu Xiulong X

Virology 20200618

Porcine epidemic diarrhea (PED) virus (PEDV) is a coronavirus that primarily infects porcine intestinal epithelial cells and causes severe diarrhea and high fatality in piglets. A77 1726 is the active metabolite of leflunomide, a clinically approved anti-rheumatoid arthritis (RA) drug. A77 1726 inhibits the activity of protein tyrosine kinases (PTKs), p70 S6 kinase (S6K1), and dihydroorotate dehydrogenase (DHO-DHase). Whether A77 1726 can control coronavirus infections has not been investigated. ...[more]

PMID: 32829915

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Project description:Chlamydiae may exist at the site of infection in an alternative replicative form, called the aberrant body (AB). ABs are produced during a viable but non-infectious developmental state termed "persistence" or "chlamydial stress." As persistent/stressed chlamydiae: (i) may contribute to chronic inflammation observed in diseases like trachoma; and (ii) are more resistant to current anti-chlamydial drugs of choice, it is critical to better understand this developmental stage. We previously demonstrated that porcine epidemic diarrhea virus (PEDV) co-infection induced Chlamydia pecorum persistence/stress in culture. One critical characteristic of persistence/stress is that the chlamydiae remain viable and can reenter the normal developmental cycle when the stressor is removed. Thus, we hypothesized that PEDV-induced persistence would be reversible if viral replication was inhibited. Therefore, we performed time course experiments in which Vero cells were C. pecorum/PEDV infected in the presence of cycloheximide (CHX), which inhibits viral but not chlamydial protein synthesis. CHX-exposure inhibited PEDV replication, but did not inhibit induction of C. pecorum persistence at 24 h post-PEDV infection, as indicated by AB formation and reduced production of infectious EBs. Interestingly, production of infectious EBs resumed when CHX-exposed, co-infected cells were incubated 48-72 h post-PEDV co-infection. These data demonstrate that PEDV co-infection-induced chlamydial persistence/stress is reversible and suggest that this induction (i) does not require viral replication in host cells; and (ii) does not require de novo host or viral protein synthesis. These data also suggest that viral binding and/or entry may be required for this effect. Because the PEDV host cell receptor (CD13 or aminopeptidase N) stimulates cellular signaling pathways in the absence of PEDV infection, we suspect that PEDV co-infection might alter CD13 function and induce the chlamydiae to enter the persistent state.

Dataset Information

Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases.

Publications

Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases.

Similar Datasets

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