Ross River virus immune evasion strategies and the relevance to Post-Viral Fatigue, and Myalgic Encephalomyelitis onset, by Brett A Lidbury in Front. Med.  Vol 8, 2021 pp 298 [doi: 10.3389/fmed.2021.662513]


Article abstract:

Ross River virus (RRV) is an endemic Australian arbovirus, and member of the Alphavirus family that also includes Chikungunya virus (CHIK). RRV is responsible for the highest prevalence human disease cases associated with mosquito-borne transmission in Australia, and has long been a leading suspect in cases of post-viral fatigue syndromes, with extrapolation of this link to Myalgic Encephalomyelitis (ME).

Research into RRV pathogenesis has revealed a number of immune evasion strategies, impressive for a virus with a genome size of 11 – 12kb (plus strand RNA), which resonate with insights into viral pathogenesis broadly. Drawing from observations on RRV immune evasion, mechanisms of relevance to long term idiopathic fatigue are featured as a perspective on infection and eventual ME symptoms, which include considerations of; (1) selective pro-inflammatory gene suppression post antibody- dependent enhancement (ADE) of RRV infection, (2) Evidence from other virus families of immune disruption and evasion post-ADE, and (3) how virally-driven immune evasion may impact on mitochondrial function via target of rapamycin (TOR) complexes.

In light of these RRV measures to counter the host immune – inflammatory responses, links to recent discoveries explaining cellular, immune and metabolomic markers of ME will be explored and discussed, with the implications for long-COVID post SARS.CoV.2 also examined.

Compelling issues on the connections between virally-induced alterations in cytokine expression, for example, will be of particular interest in light of energy pathways, and how these perturbations manifest clinically.


The history of ME features regular “outbreaks,” which have been associated with virus infections. At the time of writing, the COVID (SARS-CoV-2) pandemic has revealed a sub-population of recovered patients who have developed long-term symptoms that resemble classic ME. Therefore, a perspective is presented herein that aims to link the viral manipulation of host antiviral and inflammatory-immune responses to mitochondrial function, with TOR proteins as the critical interface between deranged cytokine expression and energy regulation.

Established for many virus families (Table 1), ADE post-infection is the particular perspective focus. ADE currently has renewed interest in relation to potential COVID vaccine safety, but in a more general context also raises questions on ME pathogenesis due to the dramatic consequences for immediate antiviral defenses, later innate immune responses, and thereafter guidance from ADE-impacted cells (e.g., antigen-presenting cells) for the formation of an appropriate adaptive immune response to support long term homeostasis.

The unraveling of the interactions between the viral manipulation of cells, bioenergetics and mitochondrial function will reveal the differences, at a cellular level, to explain why some individuals go on to develop chronic long-term health challenges like ME or long-COVID, while others do not.

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