Thread by @vipintukur

📌 A must-read article, the missing link?

What we know so far?

1-The dysregulation of innate and adaptive immunity has been recognized to play a critical role in the clinical outcome of COVID-19 patients. 1/

2-Severe evolution of COVID is thought to be driven by hyperactivated innate immunity in addition to adaptive immune defects resulting in lymphopenia & neutrophils/lymphocytes imbalance

3-A deficient IFN response has also been shown to favor or result from SARS2 infection 2/

These immunological dysregulations are thus underlying hyper-immune reactions such as the “cytokine storm” syndrome, MIS-C, dysregulation of coagulation, as well as neurological & various other manifestations 3/

The present COVID19 pandemic has thus raised many questions about the pathophysiological mechanisms explaining the many symptoms or syndromes associated with SARS-CoV-2 infection. 4/

Certain infectious agents have been shown to activate pathological processes via receptor-coupled signaling pathways, by impairing the epigenetic control and/or by directly activating endogenous retroviral elements (HERVs) present in the human genome 5/

Particularly, the resulting production of endogenous proteins of retroviral origin w/ pathogenic effects may generate clinical symptoms corresponding to the organ, tissue or cells in which they are expressed, according to the specific tropism of triggering infectious agent 6/

HERVs represent about 8% of human chromosomal sequences & comprise about 22 families independently acquired during evolution from exogenous retroviruses via an infection of germ line cells 7/

HERV-W is the coding for a protein that would normally be part of the envelope of one family of Human Endogenous Retro-Viruses, or HERVs. HERV-W encoding sequences makes up about 1% of the human genome and are part of a superfamily of repetitive and transposable elements. 8/

Commonly, viruses take pieces of their host's genome w/ them which can help them. On the other hand, hosts can also keep viral DNA in their genome which may persist if beneficial/non-deleterious. In HERVs, viral DNA integrated into the germ-line genome of a human ancestor 9/

Thus, all the progeny of the infected human ancestor would have this viral genome integrated into every cell in their bodies. This new retroviral DNA can now be passed on vertically from parents to child 10/

Abnormal expression may then become self-sustained, thus creating lifelong chronic expression from host‘ s genome copies in affected tissues, e.g., with cytokine-mediated feedback loops or, possibly, mediated by their own envelope proteins 11/

Such a sustained expression has been shown to be involved in brain lesions with lifelong expansion in patients with multiple sclerosis (MS) 12/

Different HERV envelope proteins were shown to exert major immunopathogenic and/or neuropathogenic effects in vitro and in vivo, associated with pathognomonic features of human diseases. 13/

Researchers in this study, studied whether SARS2 could activate HERV copies considered as ‘dormant enemies within’. 14/

They focused on HERV families already shown to be involved in the pathogenesis of human diseases, HERV-W & HERV-K, to evaluate their potential association w/ COVID19 & associated syndromes. 15/

This question became critical after a recent study has revealed the significant expression of HERV-W envelope protein (ENV) in lymphoid cells from COVID-19 patients, correlating with disease outcome and markers of lymphocyte exhaustion or senescence 16/

thelancet.com/journals/ebiom…

They initially addressed the potential role of SARS2 in directly triggering the activation of a pathogenic HERV protein expression as reported with other viruses in, e.g., MS and in Type 1 diabetes 17/

They analyzed HERV expression in WBCs & its possible detection in plasma of patients with COVID-19 presenting various clinical forms at early & late time-points. Lastly, they also examined this HERV expression in affected tissues from COVID-19 post-mortem samples 18/

Since a major concern beyond the initial COVID19 infectious phase is foreseen to result from the occurrence of long lasting symptoms w/ more-or-less delayed onset & often involves neurological impairment, they also examined SARS2 & HERV-W expression in brain & other organs. 19/

What did they find?

1-SARS2 can activate the production of HERV-W ENV in cultured blood mononuclear cells from a sub-group of healthy donors

2-HERV-W ENV is expressed on T lymphocytes from COVID-19 patients 20/

3-HERV-W ENV antigen is detected in all tested plasma or sera samples from severe cases in intensive care unit, but only in about 20% of PCR positive cases after early diagnosis,

4-The level of HERV-W ENV antigenemia increases with disease severity 21/

5-HERV-W ENV expression is observed by immunohistochemistry in cell-types relevant for COVID19 associated pathogenesis within affected organs & particularly in brain microglia 22/

medrxiv.org/content/10.110…

Simple language summary:

COVID19 infections trigger the production of retroviral proteins like the HERV-W envelope present in the genome stimulating production of the envelope antigen in serum, T-lymphocytes, blood mononuclear cells and is seen in many tissues post-mortem 23/

HERV-W is generally suggested to play a role in Multiple Sclerosis, cancers & autoimmunity & now maybe also might play a role in pathogenesis of COVID19 24/

It highlights the importance to further understand patients’ genetic susceptibility to HERV-W activation & the relevance of this pathogenic element as a prognostic marker & a therapeutic target in COVID 25/