BREAKING COVID-19 NEWS! Millions Unknowingly Harbor SARS-CoV-2 In Their Gut With Viral Persistence Contributing To Long COVID!

COVID-19 News: Findings from a new study clearly indicates the persistence of SARS-CoV-2 in the mucous membranes of the gastrointestinal tract of many exposed to the virus leading to distinct immunological dysfunctions and Immune impairments that contribute to Long COVID. Millions of humans are basically walking around unaware that they are reservoirs of the SARS-CoV-2 virus that is able to disarm the immune responses to their viral presence to a large degree!


Image Credit: crystal light / Shutterstock.com
 
It is now common knowledge that several months after infection with SARS-CoV-2, many individuals still exhibit symptoms: a phenomenon commonly referred to as “long COVID”.
 
In a recent study, research teams from Inserm at Université Paris-France and the University of Minho in Braga-Portugal, have shown that the manifestations and conditions of Long COVID could be explained biologically by abnormalities of the immune system associated with the persistence of the virus in the mucous membranes of the gastrointestinal tract.
 
These study findings could in the longer term pave the way for a diagnostic tool for long COVID as well as the development of new therapeutics to deal with SARS-CoV-2 viral persistence.
 
While various studies show that long COVID affects anything between 10 to 60% of people infected with SARS-CoV-2, its diagnosis and treatment remain difficult.
 
The study team of lead by Dr Jérôme Estaquier from Inserm and Dr Ricardo Silvestre form the University of Minho in Portugal, are among the first to conduct research to explain this phenomenon of Long COVID from a biological point of view.
 
Currently, few biological criteria, apart from the persistence of symptoms beyond three months after the acute infection, enable its diagnosis. Once a patient is not fully recovered after this period, they are considered to have long COVID. Without a more reliable means of diagnosis, it is difficult to offer the appropriate care.

To better understand long COVID and find diagnostic markers, the research team studied the immune systems of 164 people six months after they were infected. 
 
The study team analyzed the blood samples of 127 people, half of whom with long COVID (fatigue, shortness of breath, cough, muscle or chest pain, anxiety, etc.) and those of 37 controls who had not been infected.
 
The study team focused on certain immune cells, namely the T cells (including CD8 cells) involved in eliminating the virus, and the SARS-CoV-2 antibodies. In addition, they had blood samples that were taken during the acute phase of the disease for 72 of these patients, enabling them to retrospectively compare the level of inflammation at the early stage in those who went on to develop long COVID or not.
 
 The study findings identified a number of blood markers present six months after infection in 70-80% of the subjects with long COVID, while those same markers were rare in the subjects who had not developed it.
 
Importantly, the study findings showed that a CD8 cell subtype expressing the inflammatory protein granzyme A is present in excess, whereas ano ther CD8 subtype, this time expressing integrin b7, is present in small quantities. Yet it is the latter subpopulation that is essential for controlling viruses in the mucous membranes. In addition, virus-specific IgA antibodies are also present in excess whereas they should be rapidly eliminated if the virus is absent. These observations suggest the persistence of the virus in the body and especially in the mucous membranes of the gastrointestinal tract!
 
The study hypothesize that the SARS-CoV-2 virus could make itself at home in the intestinal mucosa as it is more “permissive” in immune terms than the rest of the body, insofar as the virus has to tolerate the bacterial flora. Other viruses, such as HIV, also use this escape strategy. Initially present in the lung mucosa, SARS-Cov-2 could therefore descend to the intestine and persist there without the immune system being able to eliminate it completely!
 
When evaluating the initial level of inflammation during the acute phase, the study team observed an association between an inflammatory response characterized particularly by very high levels of interferon IP-10 or interleukin IL-6 and the risk of going on to develop long COVID.
 
Dr Estaquier explained to COVID-19 News reporters at TMN, “This confirms clinical observations that the initial severity of COVID is associated with a higher risk of developing long COVID. One hypothesis is that individuals with more exacerbated early immunodeficiency develop more severe initial forms of COVID-19 and fail to effectively eliminate the virus that passes into the intestinal mucosa, where it settles for a long time. The immune system kind of ends up tolerating it at the cost of persistent symptoms of varying intensity and nature.”
 
The study team next plans to validate these findings in new cohorts to determine whether some of these markers could be used as a diagnostic tool.
 
Dr Estaquier said, “If measuring IgA sometime after the acute phase and potentially CD8 b7 cells was able to diagnose long COVID, doctors could make an objective diagnosis.”
 
The study findings were published in the peer reviewed journal: Nature Communications.
https://www.nature.com/articles/s41467-023-37368-1
 
The study findings besides validating SARS-CoV-2 viral persistence in the mucosal membranes of the gastrointestinal tract also showed that post-acute sequelae of COVID-19 or Long COVID is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response.
 
The study findings also showed that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop Long COVID.
 
The study indicates that Long COVID is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of Long COVID.
 
The viral persistence of SARS-CoV-2 in human body, particularly in the gastrointestinal system, nervous system and other ACE2-expressing tissues, has been widely documented, and may remain for more than four months after acute infection.
 
The continuous viral replication could impact immune cell responses contributing to local immune activation and inflammation.
 
The study team followed the hypothesis that chronic immune dysregulation could characterize Long COVID. To address this issue, the team performed both CD4+ and CD8 + T cell immunophenotyping, quantified the viral-specific antibody response and determined the cytokine signature on groups of convalescent individuals who developed or not Long COVID.
 
Interestingly, an immune CD8+ T-cell activation was observed in convalescent patients, irrespectively of developing Long COVID in which the CD4/CD8 ratio remain low upon six months of infection.
 
The study findings also showed that patients exhibit distinct profiles in type I and mucosal type III IFN compared to uninfected individuals.
 
There were higher levels of CD8+ T cells in Long COVID patients expressing the transcriptional factor Eomes. Furthermore, CD8+ T cells expressing the β7 mucosal homing receptor were low in the blood of Long COVID individuals. Consistent with mucosal immune response, the study team detected specific IgA directed to N and S proteins of SARS-Cov-2 in PASC individuals.
 
Hence the study findings highlight a model in which the persistence of viral antigens in gastrointestinal mucosa alters mucosal immune response.
 
The significant aspect of the study relates to the fact that CD8+ T cells remain activated after six months presenting higher levels of perforin and Eomes expression in Long COVID individuals.
 
Also, the study team found an attrition of the CD8+ β7 Integrin+ T cell population in peripheral blood of Long COVID individuals, concomitantly with higher plasmatic levels of IFN-λ2/3, and the presence of specific IgA to SARS-CoV-2 antigens.
 
By analyzing retrospectively, the plasma of these individuals at the early phase of infection, the study team showed that the extent of inflammation is associated with the occurrence of later Long COVID symptoms.
 
The study findings also highlighted that CD8+ T cells remain altered for a longer period, irrespective of their symptoms during acute disease.
 
The study findings demonstrated that COVID-19 patients, particularly those with Long COVID, display:
 
 -higher levels of IFN-β and IFN-λ (this latter being associated with mucosal microbial defenses)
 
-specific anti-S IgA, which are short-lived Ig compared to IgG, and mostly induced in mucosal tissues.
 
These observations associated with lower levels of blood CD8+β7 Integrin+ T cells, a marker of circulating mucosal cells strongly suggest the viral persistence of SARS-CoV-2 in gastrointestinal mucosal tissues.
 
Recent studies based on tissue biopsies or autopsies have observed the presence of SARS-CoV-2 genomic material in human tissues for at least four months after acute infection, particularly in the gastrointestinal system, the nervous system and other ACE2-rich tissues.
 
Hence, regarding CD8+ T cells, this continuous viral replication induces CD8+ T cell activation associated with local and/or systemic manifestations. Thus, IFN-λ levels correlated positively with the percentage of CD8+Eomes+ T cells and inversely with those expressing β7 integrin, particularly in Long COVID individuals.
 
It should be noted that IFN-λ is mainly produced by the epithelial tissue of intestine and lungs.
 
It was also observed that Long COVID patients had a lower level of IFN-α2 but a higher level of IFN-β. Type I interferons are crucial in eliciting an effective antiviral response, and therefore the study findings may emphasize different sources of innate cells, whereas they may induce different interferon-stimulated genes in COVID-19 individuals. Thus, the absence of IFN-α2 in Long COVID could contribute to the absence of viral control.
 
The study findings display major advances in the understanding of Long COVID in which parameters of immune activation (CD8+ β7 Integrin+ T cells and IgA) are consistent with viral persistence and are able to characterize these patients.
 
Treating viral persistence especially in the gut using newer antivirals and therapeutics may be the solution to some Long COVID manifestations.
 
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