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. 2025 Jul 2:15:1506687.
doi: 10.3389/fcimb.2025.1506687. eCollection 2025.

A bioinformatic analysis to systematically unveil shared pathways and molecular mechanisms underlying monkeypox and its predominant neurological manifestations

Amir Hossein Barjasteh  1 , Hanieh Latifi  1 , Ali Sepehrinezhad  2   3
Affiliations

A bioinformatic analysis to systematically unveil shared pathways and molecular mechanisms underlying monkeypox and its predominant neurological manifestations

Amir Hossein Barjasteh et al. Front Cell Infect Microbiol. .

Abstract

Background: Monkeypox (MPOX) is a zoonotic disease caused by the MPOX virus (MPXV). MPOX resurfaced globally in May 2022, spreading throughout six WHO regions, resulting in nearly 87,000 cases and 112 deaths. Clinical symptoms include swollen lymph nodes, fever, joint pain and several neurological complications such as headache, encephalitis, myalgia, fatigue, photophobia and seizures. Despite these manifestations, the precise mechanisms of MPXV's neurotropism remain elusive. This study aimed to explore the genetic underpinnings of MPOX-related neurological manifestations, including headache, myalgia, fatigue, and photophobia, using advanced bioinformatics tools.

Methods: Data were sourced from the GeneCards database, which is an integrated database of human genes. Genes linked to MPOX and its neurological manifestations were identified and cross-referenced to uncover shared genes between these conditions. Network visualization was created using STRING, followed by topological analysis in Cytoscape to identify key genes based on degree and betweenness centrality. Functional enrichment analysis through ToppGene provided insights into molecular functions, biological processes, and cellular components associated with these target genes. Pathway analysis was performed using WikiPathways, and cell-type-specific enrichment was conducted using Enrichr. Additionally, we predicted functional microRNAs using mirTarbase and identified potential drug candidates via the Stitch database.

Results: We identified 32 MPOX-associated genes and a large set of neurological manifestation-related genes. Ten hub genes, including CD55, CXCL1, NFKB1, CXCL8, CD4, IL6, MX1, CFH, KLRK1, and CD46 were shared between MPOX and its neurological manifestations. Five novel genes, including CFHR3, C5AR1, C3AR1, IFNA2, and CXCL3 were predicted to be associated with MPOX and its neurological complications. Gene ontology analysis highlighted biological processes such as immune regulation, viral life cycle, and lymphocyte activation, while pathway enrichment identified critical signaling mechanisms like prostaglandin signaling, toll-like receptor 4 (TLR4) signaling, complement activation, and neuroinflammation. Moreover, cell types such as T-helper cells, natural killer cells, and microglia were found to be significantly impacted by MPOX and its frequent neurological complications. We identified 11 key microRNAs associated with MPOX-neurological manifestations and repurposed eight potential drugs, offering promising therapeutic strategies.

Conclusion: This study emphasizes the central role of the complement system, immunological responses, and inflammatory pathways in the neurological manifestations of MPOX. The identification of novel genes and predicted therapeutic targets paves the way for future research and therapeutic interventions. Experimental validation is required to confirm these findings and determine the effectiveness of the proposed treatments.

Keywords: T-helper cells; bioinformatics; drug repurposing; headache; monkeypox; myalgia; natural killer cells; photophobia.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Hub genes associated with MPOX and its neurological manifestations and its reconstructed genetic networks. (A) Venn diagram represents the distribution of genes associated with MPOX and its neurological manifestations in five distinct categories. (B) Genetic network of hub genes associated with MPOX and its neurological manifestations. (C) Genetic network of hub genes associated with MPOX and its neurological manifestations and predicted five novel associated genes (white nodes). Edge colors indicating interaction types: light blue, known interactions from curated databases; pink, known interactions from experimentally determined; green, predicted interactions from gene neighborhood analysis; dark blue, predicted interactions from gene co-occurrence; yellow, interactions inferred from text mining; black, co-expression-based interactions.
Figure 2
Figure 2
Gene ontology enrichment of shared genes between MPOX and its neurological manifestations. From left to right purple, blue, and green bars represent biological process, molecular function, and cellular component respectively.
Figure 3
Figure 3
Biological pathway enrichment results for MPOX and its common neurological manifestations.
Figure 4
Figure 4
Prostaglandin signaling as a significantly enriched pathway for MPOX and its neurological manifestations. Genes associated with both MPOX and its common neurological manifestations are shown in red boxes. WikiPathways database.
Figure 5
Figure 5
Biological pathway enrichment results for MPOX and its common neurological manifestations. (A) LTF danger signal response pathway and (B) TLR4 signaling and tolerance. Genes associated to both MPOX and its common neurological manifestations are shown in red boxes. WikiPathways database.
Figure 6
Figure 6
Complement system in neuronal development and plasticity pathway as a significantly enriched pathway for MPOX and its neurological manifestations. Genes associated with both MPOX and its common neurological manifestations are shown in red boxes. WikiPathways database.
Figure 7
Figure 7
Neuroinflammation and glutamatergic signaling are outstanding pathways for MPOX and its neurological manifestations. Genes associated with both MPOX and its common neurological manifestations are shown in red boxes. WikiPathways database.
Figure 8
Figure 8
Cell-specific enrichment results for MPOX and its common neurological manifestations. Created with BioRender.com.
Figure 9
Figure 9
MicroRNA predicting enrichment results for MPOX and its common neurological manifestations. The values for the inner ring are the -log (P value) of enrichment for each miRNA which represents the statistical significance of association with MPOX-neurological manifestation genes. Created with BioRender.com.
Figure 10
Figure 10
Repurposed drug results for MPOX and its common neurological manifestations. The Enriched drugs are presented based on –Log (p-value) and their primary inputted genes. Created with BioRender.com.
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