Ross River virus immune evasion strategies and the relevance to Post-Viral Fatigue, and ME onset, 2021, Lidbury

https://www.frontiersin.org/articles/10.3389/fmed.2021.662513/abstract
(provisionally accepted - article will be published soon)

Brett A. Lidbury
Research School of Population Health, Australian National University, Australia

In Frontiers of Medicine - Infectious Diseases - Surveillance, Prevention and Treatment
Article is part of the Research Topic: Current Insights into Complex Post-Infection Fatigue Syndromes with Unknown Aetiology: the Case of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Beyond (4 Articles)


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.


(posted on behalf of @pteropus)

 

While we wait to see the published article, here's my understanding of

Paraphrasing stuff on the Wikipedia entry for ADE:

An example where this occurs is dengue fever infection. There are four different serotypes of dengue virus. Typically the first time someone is infected with, for example, serotype 1, the disease is relatively mild. They will develop antibodies which will give lifelong protections against serotype 1. They will also develop some antibodies that work to some extent against the other serotypes, although levels of these gradually decline. Some of these cross-reactive antibodies work very well, and will neutralise various serotypes of dengue virus. But some of them will bind to a virus and not neutralise it.

So, think, for example, of a person infected with serotype 2, some time after they have recovered from an infection of serotype 1. Some of the cross-reactive antibodies don't work very well. In fact they can do more harm than good, and the person ends up with a much nastier second infection, with higher levels of virus.

How do the cross-reactive antibodies do more harm than good? The antibodies bind to the virus and the antibody-virus complex is taken inside the immune cell. But the virus isn't recognised and so it isn't dismantled. And/or the virus comes loose from the poorly fitting antibody (a 'low-affinity antibody'). The virus then replicates inside the cell. The faulty antibody acts as a Trojan horse, delivering the virus into the immune cell.

There are thought to be two different mechanisms for entry into the cell:
1. the virus-antibody complex binds to the Fc-region antibody receptor (FcγR) on the immune cell. The cell then brings the virus-antibody complex inside it.
2. the virus-antibody complex activate the complement system. A C1Q complex draws the virus-antibody complex and the cell together, close enough for the virus to enter the cell.

"The viruses that can cause ADE frequently share some common features such as antigenic diversity, abilities to replicate and establish persistence in immune cells."

So, once a virus is inside an immune cell, the virus-antibody complex is thought to dial down the immune response in the host cell through the Toll-like receptor signaling pathway. Toll-like receptors cause inflammatory cytokine production when they recognise viral particles. But when the the Fc-region receptor is bound to a low affinity antibody complex, less toll-like receptors are made and their production of signalling proteins is reduced. The abstract of this paper seems to be suggesting that the immune evasion can affect mitochondrial function.

One key question I have is, does the virus need to persist in the immune cells to keep causing this dysregulation, or does it somehow have an effect that lasts after the virus has gone?