Ross River Virus Immune Evasion Strategies and the Relevance to Post-viral Fatigue, and ME Onset (Lidbury, 2021)

Pyrrhus

Senior Member
Messages
4,032
Likes
12,320
Location
U.S., Earth
If you're not from Australia, you've probably never heard of the Ross River Virus (RRV).

If you are from Australia, you may know that RRV is a common trigger of ME.

What makes RRV such a potent trigger of ME?

Brett Lidbury, of the Australian National University in Canberra, explains in detail the different ways that the Ross River Virus outwits the immune system:

Ross River Virus Immune Evasion Strategies and the Relevance to Post-viral Fatigue, and ME Onset (Lidbury, 2021)
Excerpt:
Lidbury 2021 said:
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.
 

Hip

Senior Member
Messages
16,935
Likes
37,778
The characteristic that enables Ross River virus to cause ME/CFS may be because it is an alphavirus.

Alphaviruses under certain circumstances can acquire small deletions in their genome during the acute infection of the host, and these deletions (mutations) effectively turn them into a different virus — a virus which then becomes capable of forming chronic intracellular infections.

The deletion confers alphaviruses with an ability to evade the immune response, because the deletions occur in the exact location in the RNA genome where interferon-stimulated proteins (called Ifit1 immune proteins) bind to and disable the viral RNA.

Once this interferon target location has been deleted from the RNA genome, it is thought the viral RNA becomes able to evade to the interferon Ifit1 immune response, and the RNA is then able to persist inside cells on a long-term basis.

So this may explain how Ross River virus is able to perform persistent intracellular infections which may be causing ME/CFS.



Lévêque et al detail how these genome deletions allow alphaviruses to evade the interferon immune response:
Interestingly, Hyde and colleagues demonstrated that alphaviruses, which are also single-stranded, positive-strand RNA viruses, use mutations within the 5′ noncoding region affecting secondary-structural elements of their RNAs to alter interferon-stimulated protein binding and functions (67).

Their results suggest an evasion mechanism by which a deleted virus with modified 5′ RNA secondary structures could avoid immune restriction, despite type 1 IFN secretion and interferon-stimulated gene transcription, leading to long-term virus persistence in the heart.

Lévêque et al theorized that enterovirus may use the same mechanism to evade the interferon immune response, and thereby form the chronic intracellular enterovirus infections found in ME/CFS (non-cytolytic enterovirus infections).

So this possible loss of the interferon-stimulated Ifit1 protein binding site on the viral genome could also explain how enterovirus maintains a persistent infection causing ME/CFS.