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

Discussion in 'ME/CFS research' started by Hutan, Mar 11, 2021.

  1. Hutan

    Hutan Moderator Staff Member

    Aotearoa New Zealand
    (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)

    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)
    Last edited: Mar 11, 2021
    merylg, Michelle, nick2155 and 20 others like this.
  2. Hutan

    Hutan Moderator Staff Member

    Aotearoa New Zealand
    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?
    merylg, Michelle, alktipping and 9 others like this.
  3. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

    Those steps are part of normal immune functioning. The trouble only starts if somehow the virus manages to evade the normal processing of the internalised receptor complex.

    They are suggesting persistent infection of those cells. But there can be epigenetic changes that can persist in that cell. But the question is which cells? Monocytes only last for around a few days at most (if they are not able to differentiate). Dendritic cells have a half life between 10-14 days. Macrophages can last for months, but that is heavily dependent on their linage. But this also begs the question of negative selection against those ineffective virus infected macrophages for example.
    But I don't think intracellular dysregulation of these cells is sufficient to explain the disease. I'm sure there needs to be persistent extracellular feedback loops, whether it be through paracrine signalling or cell-cell interactions.
    cfsandmore, merylg, Wonko and 7 others like this.
  4. pteropus

    pteropus Senior Member (Voting Rights)

    c2001 article about Ross River Virus, mentions Brett Lidbury

    Ross River virus tricks immune system

    With Ross River virus infecting an increasing number of Australians each year (5000-7000 cases), researchers have discovered how it tricks our body’s defences.

    New research conducted by Dr Surendran Mahalingam and Dr Brett Lidbury firstly at the University of Canberra and now at the John Curtin School of Medical Research (Australian National University) has found that the Ross River virus has developed an ingenious strategy for avoiding the body’s natural immune system.

    “The virus appears to use our own immune response to defeat the antiviral action of our body’s cells,” said Dr Mahalingam.

    Infection from Ross River virus can result in debilitating arthritis and other symptoms (such as muscle ache and lethargy), sometimes recurring over many years. How the virus causes these symptoms is still not well understood.

    Researchers were surprised to find that the Ross River virus had a better chance of withstanding immune responses if there were low levels of antibodies present. This may be a clue to how the virus operates in the human body.

    “The Ross River virus could use these antibodies to get into the body’s immune cells and sabotage their beneficial antiviral actions from deep within each cell’s molecular machinery,” Dr Lidbury said.

    “This means people are possibly more susceptible to a Ross River virus infection if they have already been exposed to the virus and have developed some antibodies against it.”

    These findings will help researchers identify possible ways of stopping the growth of the Ross River virus.

    The researchers believe this discovery with the Ross River Virus may also have implications to other disease-causing viruses such as HIV, respiratory viruses and the virus that causes dengue fever.

    shak8, cfsandmore, Michelle and 6 others like this.
  5. Andy

    Andy Committee Member

    Hampshire, UK

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