Ross River Virus Immune Evasion Strategies and the Relevance to Post-viral Fatigue, and Myalgic Encephalomyelitis Onset.

Brett A Lidbury

doi:10.3389/fmed.2021.662513

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 of 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 12 kb (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 considered. 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.

Highlights

The history of Myalgic Encephalomyelitis (ME) features outbreaks as defining events, suggesting an infectious etiology behind the cluster of symptoms experienced by affected individuals [1, 2]
Of particular interest are the observations on the dysregulation of cytokine expression in macrophages post RRVADE infection, and inflammatory responses by the host, as well as the impact on mitochondrial function
While antibody-dependent enhancement (ADE) is not the primary focus here, past investigations of ADE mechanism have identified a range of cellular pathways manipulated by viruses that may alter future cellular function, potentially leading to a long-term disturbance of homeostasis, which can lead to chronic alterations in mitochondrial function and energy regulation, manifesting as multisystem disease

Summary

INTRODUCTION

The history of Myalgic Encephalomyelitis (ME) features outbreaks as defining events, suggesting an infectious etiology behind the cluster of symptoms experienced by affected individuals [1, 2]. Of particular interest are the observations on the dysregulation of cytokine expression in macrophages post RRVADE (antibody-dependent enhancement) infection, and inflammatory responses by the host, as well as the impact on mitochondrial function. Many virus families have been observed as displaying enhanced in vitro growth post-infection due to ADE, but the impact in vivo and on disease manifestation are not currently well-understood [32,33,34]. DEN has provided a strong focus into the intracellular consequences post-ADE infection, describing other intracellular mechanisms beyond those originally identified by RRV These extend to type I IFN restriction via autophagy, SOCS3 and Syk-regulated pathways (Table 1). Inflammation impacts TOR function, and of relevance to the disruption to cytokine expression in macrophages post RRV-ADE, mTORC2 regulation is necessary for IFN-stimulated genes (ISGs) [37, 71]. Scientific reviews of ADE across virus families, see Taylor et al [32], Tirado and Yoon [33], and Porterfield [34]

DISCUSSION

CONCLUSIONS