BREAKING! COVID-19 News: Study Discovers That SARS-CoV-2 Modulates Human Endogenous Retrovirus (HERV) Transcriptome During Infection!

COVID-19 News: A new study by Italian researchers from the Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari,Italy and the Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Italy has found that that SARS-CoV-2 modulates Human Endogenous Retrovirus (HERV) transcriptome during infection and even allows allows discrimination of COVID-19 clinical stages!


 
Human endogenous retroviruses (HERVs) are a family of viruses within our genome with similarities to present day exogenous retroviruses. HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits
 
They are basically genomic relics of ancestral viral infections that threatened primates along their evolution, i.e., in the last 60 million of years. All these ancient infectious agents, which included members or all the three classes of retroviruses, have gone extinct, in most cases even before the appearance of the first humans.
 
Considering their infection and integration targeted the germ line cells, these proviral sequences have been fixed and vertically inherited throughout primates’ evolution, now constituting around the 8% of the human genome as long terminal repeat (LTR)-retrotransposons.
 
Their prolonged persistence in the primate genome exposed HERV sequences to silencing mechanisms and random mutations, leading to the loss of replication capacity.
 
However, a minority of HERVs retain some residual protein-coding potential, and in some instances their products have been domesticated for pivotal physiological functions in the host which includes the cooption of HERV Env fusogenic activity for placenta formation, the contribution of ancient retroviral Gag proteins to human brain development and architecture, and intriguingly, a pivotal role of the dispersion of endogenous retroviruses (ERV) integrations in the evolution and shaping of innate antiviral immunity networks in mammals.
https://pubmed.ncbi.nlm.nih.gov/29593697/
 
https://pubmed.ncbi.nlm.nih.gov/33922141/
 
https://pubmed.ncbi.nlm.nih.gov/26941318/
 
Besides residual protein production, growing evidence shows that many HERV sequences (even if highly defective) can still have an impact on the host through their regulatory signals, which may influence the expression of nearby cellular genes, and especially, their abundant production of RNA transcripts. The latter, beside the frequent noncoding nature, can impact cellular systems because they include viral signatures that may still be recognized as pathogen-associated molecular patterns (PAMPs) by innate immune pathways.
https://pubmed.ncbi.nlm.nih.gov/30250470/
 
It has been demonstrated that transcripts expressed by these multicopy elements can form double-stranded RNA (dsRNA) by complementary pairing, a known PAMP promptly recognized by cellular and endosomal pattern recognition receptors (PRRs), being the first-line sensors of antiviral responses (5).
ref="https://pubmed.ncbi.nlm.nih.gov/30250470/">https://pubmed.ncbi.nlm.nih.gov/30250470/
 
It is already known that such signaling triggers a cascade that leads to the nuclear induction of the interferon-I (IFN-I) pathway, with the production of inflammatory cytokines thought to be involved in the manifestation of various noninfectious disorders, including neuroinflammatory diseases and several cancers.
https://pubmed.ncbi.nlm.nih.gov/28653997/
 
https://pubmed.ncbi.nlm.nih.gov/29593697/
 
Interestingly, if on the one side HERV expression can trigger the host innate immunity, the latter is itself able to modulate HERV expression, establishing a sort of vicious circle.
 
For example, the mimicking of a microbial infection through in vivo administration of bacterial lipopolysaccharides (LPS) was shown to differentially modulate the peripheral blood mononuclear cell (PBMCs) expression of 4,607 HERV and mammalian apparent LTR retrotransposon (MaLR) sequences, which showed a general colocalization with cellular genes involved and/or modulated in the innate immune response.
https://pubmed.ncbi.nlm.nih.gov/32669333/
 
In the same light, adaptive immune responses evoked by antiviral vaccination have also been shown to influence HERV expression, showing a dynamic modulation of HERV transcripts according to the different stages of antibody production.
https://pubmed.ncbi.nlm.nih.gov/34062989/
 
 In addition, even with lower genetic resolution, several other studies reported the general modulation of individual HERV group expression in the presence of several viral infections, including among others, HIV, hepatitis C virus (HCV), influenza and herpesviruses.
https://pubmed.ncbi.nlm.nih.gov/17263641/
 
https://pubmed.ncbi.nlm.nih.gov/32759845/
 
https://pubmed.ncbi.nlm.nih.gov/32340287/
 
https://pubmed.ncbi.nlm.nih.gov/32485981/
 
https://pubmed.ncbi.nlm.nih.gov/24478419/
 
https://pubmed.ncbi.nlm.nih.gov/23028727/
 
https://pubmed.ncbi.nlm.nih.gov/26071331/
 
To date, very few studies have assessed the transcriptional modulation of HERV loci by SARS-CoV-2 infection or, in light of the predominant inflammatory environment, their specific pattern of expression according to COVID-19 clinical stages and disease severity.
 
These interplays are highly relevant, especially considering that HERV transcriptional activation may sustain and amplify the inflammatory activation exerted by COVID19, which is a major cause of severe symptoms and death, as well as of permanent sequelae in convalescent patients.

The Italian study team report here the first high-throughput analysis of HERV loci expression along SARS-CoV-2 infection, as performed with peripheral blood mononuclear cells (PBMCs).
 
Although such cells are not directly infected by the virus, they have a crucial role in the plethora of inflammatory and immune events that constitute a major hallmark of COVID-19 pathogenesis.
 
The study findings provide a novel and exhaustive picture of HERV expression in PBMCs, revealing specific modulation patterns according to the disease condition and the concomitant immune activation.
 
To the study team’s knowledge, this is the first set of deHERVs whose expression is dynamically modulated across COVID-19 stages, confirming a tight interplay between HERV and cellular immunity and revealing specific transcriptional signatures that can have an impact on the disease clinical manifestation and outcome.
 
The study findings were published in the peer reviewed journal: Microbiology Spectrum (A Journal Of The American Society For Microbiology).
https://journals.asm.org/doi/10.1128/spectrum.02516-22
 
Corresponding author, Dr Enzo Tramontano, a Professor from the Laboratory of Molecular Virology, University of Cagliari told COVID-19 News reporters at Thailand Medical News, “COVID-19 infection is known to trigger an important inflammatory response, which has a major role in COVID-19 pathogenesis. In infectious and inflammatory contexts, the modulation of human endogenous retroviruses (HERV) has been broadly reported, being able to further sustain innate immune responses due to the expression of immunogenic viral transcripts, including double-stranded DNA (dsRNA), and eventually, immunogenic proteins.”
 
He further added, “In order to gain insights on this poorly characterized interplay, our study team performed a high-throughput expression analysis of ~3,300 specific HERV loci in the peripheral blood mononuclear cells (PBMCs) of 10 healthy controls and 16 individuals being either convalescent after the infection (6) or retesting positive after convalescence (10) (Gene Expression Onmibus [GEO] data set GSE166253).”
 
He continued, “Our study findings showed that the exposure to SARS-CoV-2 infection modulates HERV expression according to the disease stage and reflecting COVID-19 immune signatures. The differential expression analysis between healthy control (HC) and COVID-19 patients allowed us to identify a total of 282 differentially expressed HERV loci (deHERV) in the individuals exposed to SARS-CoV-2 infection, independently from the clinical form. In addition, 278 and 60 deHERV loci that were specifically modulated in individuals convalescent after COVID19 infection (C) and patients that retested positive to SARS-CoV-2 after convalescence (RTP) as individually compared to HC, respectively, as well as 164 deHERV loci between C and RTP patients were identified.”
 
The study team reported that the identified HERV loci belonged to 36 different HERV groups, including members of all three classes. The present study provides an exhaustive picture of the HERV transcriptome in PBMCs and its dynamic variation in the presence of COVID-19, revealing specific modulation patterns according to the infection stage that can be relevant to the disease clinical manifestation and outcome.
 
It should be noted that HERV transcriptional activation, as observed in different infectious and autoimmune diseases as well as in tumorigenesis may sustain and amplify the inflammatory activation exerted by COVID-19, having the ability to be sensed as PAMPs by cellular PRRs and evoke an innate immune response.
 
The study findings also confirm, on the one hand, that SARS-CoV-2 infection is associated with a long-term effect on the host, which is still evident after viral clearance and in a cellular population being not directly infected by the virus, and on the other hand, that such modulation has different and specific signatures in actively infected patients and individuals recovered from the infection when considering HERV expression.
 
The study findings also has implications about the potential risk of cancers and tumors and potentially accelerated progression in Post COVID individuals!
 
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