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Role of p38α MAPK in Monkeypox Virus Replication and Neuroinvasion: Implications for Therapeutic Targeting

ABSTRACT: Monkeypox virus (MPXV), a re-emerging zoonotic orthopoxvirus, has been increasingly linked to neurological manifestations in both patients and in experimental models. However, the mechanisms underlying MPXV-induced neural injury remain unclear. In non-human primate (NHP) model, we observed MPXV replication across multiple brain regions beginning at 7 days post-infection (dpi), peaking in the medulla oblongata at 14 dpi, and largely clearing by 21 dpi. Viral RNA was detected in the choroid plexus and cerebral microvascular endothelium, suggesting MPXV crosses the blood-brain barrier (BBB) via vascular routes. MPXV infected various neural cell types, including neurons, astrocytes, microglia, and neural stem cells, triggering neuroinflammatory responses. In human pluripotent stem cell (iPSC)-derived neural progenitor cells, neurons, and astrocytes, productive MPXV infection was demonstrate across all cell types. Astrocytes exhibited dose-dependent susceptibility and pro-inflammatory cytokine induction. Transcriptomic analysis revealed the activation of the MAPK signaling pathway. Through CRISPR-Cas9 screening, we identified p38 MAPK as a key regulator of MPXV replication. Pharmacological inhibition of p38 MAPK (SB203580, VX-745) significantly reduced viral replication and pro-inflammatory cytokine production across various cell models, including glioblastoma cells, primary astrocytes, A549 epithelial cells, and brain organoids. Mechanistically, p38 MAPK phosphorylated the viral envelope protein VP37 at T220, enhancing its membrane association and trans-Golgi network localization, thereby facilitating viral maturation. Additionally, p38 MAPK suppressed STING phosphorylation and downstream interferon signaling, aiding immune evasion. Extending these findings, p38 MAPK activity was found to be essential for vaccinia virus (VACV-VG9) replication. Collectively, our study uncovers p38 MAPK as a central host dependency factor for MPXV replication and neuroinflammation, highlighting p38 inhibition as a promising broad-spectrum antiviral strategy. These findings not only provide mechanistic insights into MPXV neuropathogenesis but also identify a clinically actionable therapeutic target with potential efficacy against multiple poxvirus infections.

ORGANISM(S): Homo Sapiens

SUBMITTER: Qiangming Sun

PROVIDER: PXD071786 | iProX | Tue Dec 09 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections. Global gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression. HUVEC were infected with FPV in the presence or absence of a p38 MAP kinase inhibitor

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Role of p38α MAPK in Monkeypox Virus Replication and Neuroinvasion: Implications for Therapeutic Targeting

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