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Review
. 2021 Jun 18:8:688486.
doi: 10.3389/fmed.2021.688486. eCollection 2021.

The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review

Affiliations
Review

The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review

Adam J O'Neal et al. Front Med (Lausanne). .

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades. This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.

Keywords: RT-PCR; cell culture; chronic fatigue syndrome; chronic infection; enterovirus; immunohistochemistry; myalgic encephalomyelitis; serology.

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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
Representative enterovirus genome structure with emphasis on 5′UTR Domain I and genome replication. (A) Graphical depiction of EV genome as well as proteolytic processing to produce all structural and non-structural proteins. Number ranges indicate nucleotide positions for domains 1–7 in the 5′UTR of CVB4. (B) 2D illustration of CVB4 Domain I secondary structure. Numbers indicate nucleotide positions. (C) From (23) by license: Creative Commons Attribution 4.0 International. An integrated model for enterovirus replication. Negative-strand synthesis is initiated by circularization of the positive-strand genome via a protein-protein bridge through the interaction of the ternary complex at the 5′-end (3CD and PCBP bound to the cloverleaf structure) and PABP bound to the 3′-poly(A)tail (I. + II.). CRE-mediated VPg-pUpU acts as primer of the reaction and the polymerase 3D synthesizes the new negative-strand (III.), resulting in a double-stranded intermediate (RF) (IV.). The positive-negative duplex RNA intermediate unwinds, so that the cloverleaf structure at the 5′-end of the positive-strand can form. 3CD and PCBP bind to the cloverleaf to form a ternary complex, which, in turn, will initiate positive-strand synthesis on the 3′-end of the negative-strand (V.). The primer, VPg-pUpU, is recruited and binds to the 3′-terminal AA of the negative strand, and the new positive-strand is synthesized by the polymerase, 3D (VI.).
Figure 2
Figure 2
Schematic showing primer binding sites across an enteroviral genome. 5′UTR domains are indicated by roman numerals. Numbers on top of the representative genome indicate nucleotide position. Forward and reverse primers as well as probes (if applicable) are indicated across all 8 PCR methodologies used across enterovirus-related ME/CFS studies. Dark blue arrows indicate forward primers, dark green arrows indicated reverse primers, second round primers used in nested PCR approaches are indicated by light blue (forward) and light green (reverse) arrows. Red bars indicate probes and the one gray arrow indicates a primer used in the primary reverse transcription step.

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