Mucosal Viruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Missing Piece of the Puzzle?

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition without a definitive aetiology, no reliable diagnostic test, and no proven effective treatment. Despite most patients reporting a post-viral onset of illness, findings to date are conflicting on whether a single virus or multiple viral triggers are involved. Most studies to date have focused on detecting viruses in blood and circulating immune cells with relatively few investigating the presence of viruses in mucosal sites. In this review, we propose that this represents a critical gap in understanding the pathophysiology of ME/CFS knowledge, as mucosal tissues are primary entry points for most pathogens and often serve as reservoirs where viruses may persist. Consequently, they represent ideal niches for identifying persistent infections in ME/CFS. Emerging evidence from saliva and other mucosal samples in ME/CFS patients is consistent with this proposal and that latent viruses can persist and periodically reactivate in mucosal tissues from where they can potentially contribute to immune dysregulation, chronic inflammation, and increased symptom severity that defines ME/CFS.

Keywords: DNA viruses; RNA viruses; mucosal reservoirs; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); viral persistence.

Figure 1

Conceptual schematic of the proposed role of persistent mucosal viruses in the aetiology of ME/CFS. Mucosal cells, such as epithelial cells, can serve as reservoirs for persistent viruses, potentially supporting viral replication under pathological conditions including stress, inflammation, microbiota dysbiosis, epithelial injury, or impaired immune surveillance [50]. These infected mucosal cells can release viral particles both apically (into the lumen) and basolaterally, promoting further infection and systemic spread [50,51,52]. Persistent mucosal viruses may also cross the disrupted gut intestinal epithelial barrier (leaky gut), activating dendritic cells and macrophages within the lamina propria, promoting CD4 Th1 and Th17 responses. Th1 cytokines, IFN-γ and TNF-α, activate M1 macrophages, driving the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) into systemic circulation. These cytokines inhibit Th2 differentiation or the production of immune tolerance promoting cytokines resulting in a more pro-inflammatory state dominated by Th1/Th17 responses, which further exacerbates inflammation. Th17-derived IL-17 and IL-22 promote neutrophil recruitment and the release of antimicrobial peptides (AMPs) such as lysozymes and defensins with chronic neutrophil activation leading to epithelial damage and degradation and thinning of the mucus layer. Disruption of the epithelial barrier facilitates viral translocation which may promote a feed-forward inflammatory loop perpetuating local and systemic immune dysregulation observed in ME/CFS. (Created in BioRender. Perera, K. (2025) https://BioRender.com/rxje1b4, accessed on 10 November 2025).

Figure 2

A proposed mechanism linking latent mucosal viral reservoirs to systemic inflammation and neuroimmune symptoms observed in ME/CFS. Latent viruses such as EBV, HHV6/7, and enteroviruses persist in mucosal tissues. Reactivation triggered by internal or environmental stressors, combined with immune-mediated damage to the epithelial barrier, disrupts its integrity. Immune spillover occurs as local pro-inflammatory mediators (e.g., cytokines) and immune responses escape the mucosal compartment, leading to the release of cytokines and viral leakage into deeper tissues and bloodstream causing viraemia. The resulting systemic inflammation promotes chronic low-grade immune activation. Concurrent viral infection in endothelial cells (e.g., herpesviruses) may induce endothelial dysfunction and cause vascular abnormalities, further exacerbating systemic inflammation. Circulating neuroimmune factors could reach the central nervous system, causing neuroinflammation. Disruption of the hypothalamic–pituitary–adrenal (HPA) axis impairs cortisol production and stress regulation, often because of ongoing inflammation. Persistent viral activity and inflammation can also activate HERVs further amplifying immune dysregulation and contributing to chronic infection. All these factors drive key ME/CFS symptoms, including fatigue, cognitive dysfunction (brain fog), post-exertional malaise, and sleep disturbances. This model highlights how mucosal reservoirs may contribute to systemic immune dysregulation in ME/CFS. (Created in BioRender. Carding, S. (2025) https://BioRender.com/5bmmgg5, accessed on 10 November 2025).