Review SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC), 2023, Proal et al

[EndME]

SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC)

Abstract
Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA—potentially capable of being translated to produce viral proteins—persist in tissue as a ‘reservoir’. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.

https://www.nature.com/articles/s41590-023-01601-2#MOESM1

 

[EndME]

It's nice to see all the "big" Long-Covid researchers like Iwasaki, Deeks, Henrichs, Ely, Wherry, Peluso et al, come together and put their name behind this paper. I'm sure this paper will be cited hundreds of times. Let's hope it also has proper implications.

 

[Jaybee00]

Another AP paper with no data. Shocker!

 

[Jaybee00]

It's nice to see all the "big" Long-Covid researchers like Iwasaki, Deeks, Henrichs, Ely, Wherry, Peluso et al, come together and put their name behind this paper. I'm sure this paper will be cited hundreds of times. Let's hope it also has other implications.

I don’t agree—this strikes me more as hive-mind stuff. They would be better off doing *actual research studies*.

 

[EndME]

I don’t agree—this strikes me more as hive-mind stuff. They would be better off doing *actual research studies*.

I can understand that, but this type of stuff doesn't really take very long nor does it require any funding. Someone writes it up and the others read over it. I definitely much prefer biomedical studies as well, but even these studies can have an impact, albeit very small.

 

[Hutan]

I agree with you both. When I saw the title, I was hoping for a biomedical study that might have found something, so was disappointed to see it's just a review. But, I guess it's legitimate to read some papers and make some conclusions, including related to what needs to be studied next, and then write about what you are thinking. I guess that's especially so if you have a role in allocating funding to new research projects. It gives donors an idea of whether it's worth funding researchers.

The devil is in the detail. A lot of these sorts of papers end up being full of confirmation bias.

In Nature immunology, so good for Long covid visibility. And, with 33 authors, it's probably good for strengthening researcher networks and coordination.

There is precedence for the persistence of other single-stranded RNA viruses after acute illness. RNA from Ebola virus11,12,13, Zika virus14, enteroviruses15,16 and measles virus17,18 has been identified in tissue obtained months or years after initial infection. In multiple instances, these viral reservoirs have been shown to be capable of driving chronic disease19,20. In the case of Ebola virus disease, new outbreaks have been sparked by individuals carrying persistent Ebola virus years after acute illness21,22, and there are multiple reports of sexual transmission of Zika virus many months after recovery from acute disease23.

One autopsy study identified SARS-CoV-2 RNA and protein in dozens of body tissues and brain obtained at least 31 d and up to 230 d after COVID-19 symptom onset31. Over 50% of these cases had persistent RNA in lymph nodes from the head and neck, and from the thorax, sciatic nerve, ocular tissue and in most sampled regions of the central nervous system (CNS) including the cervical spinal cord, brainstem and olfactory nerve.

SARS-CoV-2 RNA or protein has been identified in tissue months after initial illness despite negative results via standard nasopharyngeal PCR testing and/or a lack of detection in peripheral blood from the same individual31,33. These observations suggest that SARS-CoV-2 persistence occurs largely in tissues. Indeed, most human tissue types are dense with cells expressing the angiotensin 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors SARS-CoV-2 uses for cell entry. A similar pattern has been documented with other RNA viruses associated with chronic sequelae in a subset of survivors34,35,36. Immune responses against SARS-CoV-2 RNA and protein, including those indicative of persistence, can also be localized to tissue and are not necessarily apparent in the blood of the same individual37.

 

[Hutan]

A major gap in the field is the absence of PASC-specific autopsy data.

I think this (tissue banks) might be something post-infection disease advocates need to work on.

Another team detected RNA encoding SARS-CoV-2 spike protein in colorectal tissue collected from five patients with PASC from 158 days to 676 days following the initial COVID-19 illness.

Goh et al. identified SARS-CoV-2 RNA and N protein in the skin, appendix and breast tissue of two individuals who exhibited PASC symptoms 163 and 426 d after acute COVID-19 disease39.

In addition to persisting as soluble proteins in circulation, SARS-CoV-2 proteins, including spike, have been detected in PASC plasma in extracellular vesicles (EVs).

For example, Swank et al. reported multiple PASC cases in which spike protein was identified in plasma of the same individual at some time points but not others41. These findings suggest it may be possible that SARS-CoV-2 in a reservoir could have periods of inactivity and resume protein production and/or replication at other times such as when immune control is altered.

A study of survivors with post-Ebola syndrome suggests that the activity of persistent viral RNA in reservoir sites can change over time. Adaken et al. reported declines and subsequent rises—or a ‘decay–stimulation–decay’ pattern—in neutralizing antibody levels in the plasma of Ebola virus disease survivors46. This periodic neutralizing antibody resurgence likely corresponds to periods of more active replication in Ebola virus reservoir sites, followed by periods of relative inactivity. Similar waves of recurrent immune activation consistent with periodic increases in immune stimulation by viral proteins have also been documented in measles47. Further interrogating such relationships in PASC is warranted.

 

[Hutan]

I've just skimmed the rest - a lot is covered. I think it's a decent review, a handy resource for researchers.

Regimens for other RNA viruses capable of persistence (for example, human immunodeficiency virus and hepatitis C virus) require multiple drugs for robust long-term benefit.

Treatment with antivirals or combinations of antivirals and immune-modulating agents during acute COVID-19 may also prevent PASC by decreasing or eliminating virus that might otherwise persist in a reservoir. Acute COVID-19 antiviral clinical trials should consequently be designed to capture the impact of treatment on PASC development. For example, Xie et al. estimated the effect of the antiviral nirmatrelvir (versus control) on covariate-standardized hazard ratio and absolute risk reduction of a prespecified panel of 12 post-acute COVID-19 outcomes after 90 d (ref. 109). They found that in individuals with SARS-CoV-2 infection with at least one risk factor for progression to severe COVID-19 illness, nirmatrelvir treatment within 5 d of a positive COVID-19 test was associated with reduced risk of PASC regardless of history of prior infection and vaccination status.

 

[SNT Gatchaman]

Box 1: Major areas of opportunity for research into a SARS-CoV-2 reservoir in PASC

• Which PASC cell and tissue types harbor SARS-CoV-2 RNA or protein? Is there a preference for persistence in certain cell or tissue types?

• Is SARS-CoV-2 RNA identified in PASC samples transcriptionally active, translating, replicating or infectious?

• Is the presence of a SARS-CoV-2 reservoir sufficient to drive PASC symptoms? Are SARS-CoV-2 RNA and proteins also identified in samples collected from post-COVID-19 individuals without PASC? If yes, what factors differentiate SARS-CoV-2 persistence in PASC from persistence in asymptomatic individuals?

• Do particular classes of symptoms tend to be driven by the location of the reservoir—for example, dyspnea from a lung reservoir or gastrointestinal symptoms from a gut reservoir?

• Do measurements of SARS-CoV-2 protein or antibody responses in body fluids correlate with SARS-COV-2 persistence in tissue?

• Can the transcriptional program of circulating immune cells be used as a biosensor of SARS-CoV-2 persistence in tissue? Does T cell exhaustion correlate with SARS-CoV-2 persistence in PASC?

• Are neutralizing antibody responses qualitatively different in patients with PASC?

• By what mechanisms can SARS-CoV-2 evade immune detection? Do such mechanisms differ by cell or tissue type, or by viral variant? Do viral mutations and selection contribute to persistence?

• Can the spike protein travel via EVs into the bloodstream?

• Does a SARS-CoV-2 reservoir or protein contribute to fibrin/amyloid microclotting, platelet activation or related vasculature issues in PASC?

• Does a SARS-CoV-2 reservoir in PASC correlate with the reactivation of other pathogens such as herpesviruses?

• Does a SARS-CoV-2 reservoir in PASC correlate with changes in human endogenous retrovirus activity?

• Can a SARS-CoV-2 reservoir alter the local transcriptome or epigenome?

• Does a SARS-CoV-2 reservoir in PASC correlate with the disruption of microbiome composition or activity? If so, is disruption a cause or consequence of PASC?

• Is a SARS-CoV-2 reservoir associated with host epithelial barrier breakdown in PASC? Does this facilitate the translocation viral protein or bacterial/fungal organisms into blood?

• Can SARS-CoV-2 persistence or the reactivation of other latent pathogens lead to cross-reactive antibody responses in PASC blood or tissue?

Edit: spacing

 

[dave30th]

They would be better off doing *actual research studies*.

It's not an either-or situation here. I think a high-profile paper like this in a Nature journal will get a lot of attention and gives great credibility to the research actually going on. That so many of the major researchers have signed onto this makes it that much more forceful a statement.

 

[Ash]

It's not an either-or situation here. I think a high-profile paper like this in a Nature journal will get a lot of attention and gives great credibility to the research actually going on. That so many of the major researchers have signed onto this makes it that much more forceful a statement.

That a very good point.
Thanks for pointing that out, impatiently waiting for some proof of something, that could be important to potential treatments, can mean over looking the mini advancements, for me at least.

I have little faith in researchers generally (except decode) being able to get the resources to to prove/disprove.

But hopefully that will change, as biomedical research in this area gains a profile.

 

[Andy]

Trial By Error: Call for Retraction of Cochrane Review from Science For ME; Overview of Viral Persistence in Long Covid; Senators United on Long Covid

https://virology.ws/2023/09/07/tria...-in-long-covid-senators-united-on-long-covid/