Virus-induced p38 MAPK activation facilitates viral infection

Abstract

Rationale: Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. Methods: The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. In vitro kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. Results: HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Conclusion: Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.

The Role of Non-Structural Protein NSs in the Pathogenesis of Severe Fever with Thrombocytopenia Syndrome

“…For example, SFTSV triggers mitochondrial dysfunction and NLRP3 inflammasome activation [ 38 ]. Moreover, the virus activates p38 mitogen-activated protein kinase (MAPK) signaling pathway [ 39 ], which plays a crucial role in many biological processes, such as cell proliferation and apoptosis, inflammation, aging and tumorigenesis [ 40 , 41 , 42 ]. Additionally, SFTSV causes a global disruption of naïve T-cell differentiation, and antibody class switching [ 34 ], resulting in impeded humoral immune responses.…”

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

“…Importantly, the observed effects of MAPK inhibitors on MAYV replication did not appear to result from virucidal activity by these compounds. Previous reports have shown that p38 inhibition affects the replication of viruses from different families, among them, enterovirus 71, hepatitis C virus, influenza virus, Chikungunya virus and SARS-CoV-2 [27,35,[51][52][53].…”

Atypical p38 Signaling, Activation, and Implications for Disease

“…Inhibition of TAB1-dependent p38 activation impaired hepatitis C virus (HCV) assembly and viral replication. This was also confirmed for severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 127 ]. Indeed, the p38 inhibitor losmapimod is currently in a clinical trial to treat SARS-CoV-2 (ClinicalTrials.gov ID: NCT04511819).…”