Tag: viral persistence

Inflammation-associated gut microbiome in postacute sequelae of SARS-CoV-2 points towards new therapeutic targets

We read with interest the recent report by Liu et al1 describing faecal microbiome differences with postacute sequelae of SARS-CoV-2 (PASC), commonly referred to as ‘Long-COVID’. We have previously reported elevated levels of SARS-CoV-2-specific T cells with PASC compared with resolved COVID-19 (RC; no lingering symptoms at the time of sample collection) that correlated with increased levels of the inflammatory marker IL-6, suggesting that elevated inflammation in PASC may be related to immune response to residual virus.2 Although several studies have reported gut microbiome differences during acute COVID-19,3 PASC has received less attention. We, thus, sought to characterise gut microbiome differences in PASC versus RC using faecal samples from our study2 and to relate these differences to inflammation.

The faecal microbiome was evaluated using 16S rRNA gene sequencing. Plasma levels of inflammatory markers IL-6 and C reactive protein (CRP) were measured with ELISA (see online supplemental methods). Cohort information is in table 1. IL-6 and CRP were elevated with PASC (figure 1A). Gut microbiome composition did not significantly differ between the PASC and RC cohorts (PERMANOVA; p=0.087; figure 1B), but did correlate with IL-6 and CRP levels (Adonis; IL-6 p=0.03; CRP p=0.01). IL-6 and CRP also correlated with PC1 from a principal coordinates analysis (figure 1C,D), suggesting a relationship between microbiome composition and inflammation in PASC. Using SELBAL,4 which identifies ratios or ‘Balances’ of microbes that can differentiate between groups, we found that the faecal microbiomes of individuals with PASC had a lower ratio of an amplicon sequence variant (ASV) highly related to Faecalibacterium prausnitzii over ASVs related to species in the genus Bacteroides (B. dorei, B. massiliensis and B. thetaiotaomicron) (figure 1E), which provided an area under the curve (AUC) of 0.863 for differentiating individuals with PASC from RC. Balance values also negatively correlated with IL-6 (r=−0.44, p=0.01). These microbiome differences are consistent with Liu et al,1 who also reported higher levels of Bacteroides (B. vulgatus specifically) and lower F. prausnitzii with PASC. Liu et al also reported higher Ruminococcus gnavus with PASC, and lower Collinsella aerofaciens, and Blautia obeum. Interestingly, an ASV highly related to R. gnavus (100% identity over V4 read) correlated positively with IL-6 and ASVs related to F. prausnitzii (98.7% ID), C. aerofaciens (100% ID) and B. obeum (100% ID) all negatively correlated with IL-6 and/or CRP levels in our study (online supplemental table 1). Thus, our results are consistent with those of Liu et al and extend their findings by showing associations between the microbiome and markers of systemic inflammation.

Read the rest of this letter HERE.

Source: Carneiro VL, Littlefield KM, Watson R, Palmer BE, Lozupone C. Inflammation-associated gut microbiome in postacute sequelae of SARS-CoV-2 points towards new therapeutic targets. Gut. 2023 Jan 30:gutjnl-2022-328757. doi: 10.1136/gutjnl-2022-328757. Epub ahead of print. PMID: 36717218. https://gut.bmj.com/content/early/2023/01/29/gutjnl-2022-328757 (Full text)

SARS-CoV-2 infection and persistence in the human body and brain at autopsy

Abstract:

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14.

Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset.

We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract.

Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

Source: Stein SR, Ramelli SC, Grazioli A, Chung JY, Singh M, Yinda CK, Winkler CW, Sun J, Dickey JM, Ylaya K, Ko SH, Platt AP, Burbelo PD, Quezado M, Pittaluga S, Purcell M, Munster VJ, Belinky F, Ramos-Benitez MJ, Boritz EA, Lach IA, Herr DL, Rabin J, Saharia KK, Madathil RJ, Tabatabai A, Soherwardi S, McCurdy MT; NIH COVID-19 Autopsy Consortium; Peterson KE, Cohen JI, de Wit E, Vannella KM, Hewitt SM, Kleiner DE, Chertow DS. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022 Dec;612(7941):758-763. doi: 10.1038/s41586-022-05542-y. Epub 2022 Dec 14. PMID: 36517603; PMCID: PMC9749650. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749650/ (Full text)

Lingering SARS-CoV-2 in Gastric and Gallbladder Tissues of Patients with Previous COVID-19 Infection Undergoing Bariatric Surgery

Abstract:

Background: Lingering severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gut tissue might be a source of infection during bariatric surgery. This study aimed to confirm the presence of SARS-CoV-2 nucleocapsid in gastric and gallbladder tissues removed during bariatric surgery in individuals previously infected with coronavirus disease 2019 (COVID-19) who had negative polymerase chain reaction results prior to the surgery.

Methods: Gastric and gallbladder specimens from 80 patients who underwent bariatric surgery between November 2021 and May 2022 and had a history of COVID-19 infection with gastrointestinal symptoms were examined for the presence of lingering SARS-CoV-2 nucleocapsid proteins using immunohistochemistry.

Results: Gastric specimens from 26 (32.5%) patients and 4 (100%) cholecystectomy specimens showed positive cytoplasmic staining for the anti-SARS-CoV-2 nucleocapsid protein in surface mucosal epithelial cells. The mean age was 37.8 ± 10.3 years. The average body mass index was 44.2 ± 7.0 kg/m2; most of the patients were females (71.3%). The positive staining group was significantly younger than the negative staining group (p = 0.007). The full-dose vaccination rate was 58.8%, with a median of 91 days after the last vaccine dose. A positive serological anti-spike IgG response was observed in 99% of the patients. The median time between initial COVID-19 infection and surgery was 274 and 380 days in the positive and negative staining groups, respectively (p = 0.371).

Conclusion: Gastric and gallbladder tissues can retain SARS-CoV-2 particles for a long time after COVID-19 infection, handling stomach specimens from patients during an operation must be done with care, as we usually do, but now with the knowledge that in 1/3 of patients they can be present. Performing LSG on post-COVID patients did not seem to increase perioperative morbidity.

Source: Hany, M., Zidan, A., Gaballa, M. et al. Lingering SARS-CoV-2 in Gastric and Gallbladder Tissues of Patients with Previous COVID-19 Infection Undergoing Bariatric Surgery. OBES SURG (2022). https://doi.org/10.1007/s11695-022-06338-9  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9628579/ (Full text)

SARS-CoV-2 infection and persistence throughout the human body and brain

Abstract:

COVID-19 is known to cause multi-organ dysfunction1-3 in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain3,6-14.
We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple extrapulmonary tissues early in infection.
Further, we detected SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.
Source: Daniel Chertow, Sydney Stein, Sabrina Ramelli et al. SARS-CoV-2 infection and persistence throughout the human body and brain, 20 December 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1139035/v1] https://www.researchsquare.com/article/rs-1139035/v1 https://www.nature.com/articles/s41586-022-05542-y (Full text)

Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19

Abstract:

The World Health Organization has defined long COVID-19 (LC) as a condition where patients exhibit persistent symptoms over time after its acute phase, which cannot be explained by alternative diagnosis. Since we have previously reported residual viral antigens in tissues of convalescent patients, we now aim to assess the presence of such antigens in post-convalescent tissues. Here, we established the presence of residual virus within the appendix and breast tissue of 2 patients who exhibited LC symptoms, 175 to 462 days upon positive diagnosis, using immunohistological techniques. We observed positive staining for viral nucleocapsid protein (NP) in the appendix, and tumour-adjacent region of the breast, but not within the tumour via multiplex immunohistochemistry. Notably, with RNAscope, both positive-sense and negative-sense (replicative intermediate) viral RNA were detected. As a single-stranded virus, SARS-CoV-2, have to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, the detection of negative-sense viral RNA suggests ongoing viral replication.
While viral RNA and antigen from gastrointestinal and stool samples of convalescent patients has been extensively reported, we believe this is the first study to detect viable virus. Furthermore, our positive finding in the breast tissue also corroborated with recent reports that immunocompromised patients had also experienced LC symptoms and persistent viral replication. Overall, our findings, along with emerging LC studies, raises the possibility of the gastrointestinal tract functioning as a reservoir.
Source: Denise Goh, Jeffrey Chun Tatt Lim, Sonia Bilbao Fernández et al. Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19, 07 June 2022, PREPRINT (Version 2) available at Research Square https://doi.org/10.21203/rs.3.rs-1379777/v2  (Full text available as PDF file)

Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome

Abstract:

Background: Long COVID (coronavirus disease 2019) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems. In this report, we propose a model for the pathophysiology of the long COVID presentation based on increased proinflammatory cytokine production that results from the persistence of the SARS-CoV-2 virus or one of its molecular components. Associated with this hyperproduction of inflammatory cytokines is a heightened activity of nuclear factor κ B (NF-κB) and p38 mitogen-activated protein kinase signaling pathways that regulate cytokine production.

Objective: The purpose of the present report was to review the causes of long COVID syndrome and suggest ways that can provide a basis for a better understanding of the clinical symptomatology for the of improved diagnostic and therapeutic procedures for the condition.

Methods: Extensive research was conducted in medical literature data bases by applying terms such as “long COVID” associated with “persistence of the SARS-CoV-2 virus” “spike protein’ “COVID-19” and “biologic therapies.”

Results and Conclusions: In this model of the long COVID syndrome, the persistence of SARS-CoV-2 is hypothesized to trigger a dysregulated immune system with subsequent heightened release of proinflammatory cytokines that lead to chronic low-grade inflammation and multiorgan symptomatology. The condition seems to have a genetic basis, which predisposes individuals to have a diminished immunologic capacity to completely clear the virus, with residual parts of the virus persisting. This persistence of virus and resultant hyperproduction of proinflammatory cytokines are proposed to form the basis of the syndrome.

Source: Buonsenso D, Piazza M, Boner AL, Bellanti JA. Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome. Allergy Asthma Proc. 2022 May 1;43(3):187-193. doi: 10.2500/aap.2022.43.220018. PMID: 35524358. https://pubmed.ncbi.nlm.nih.gov/35524358/ https://www.ingentaconnect.com/content/ocean/aap/2022/00000043/00000003/art00003;jsessionid=pp9ea7gev7kv.x-ic-live-01#  (Full text available as download)

Chronic fatigue syndrome, the immune system and viral infection

Abstract:

The chronic fatigue syndrome (CFS), as defined by recent criteria, is a heterogeneous disorder with a common set of symptoms that often either follows a viral infection or a period of stress. Despite many years of intense investigation there is little consensus on the presence, nature and degree of immune dysfunction in this condition.

However, slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF) α are likely present. Additionally, impaired natural killer cell function appears evident. Alterations in T cell numbers have been described by some and not others.

While the prevalence of positive serology for the common herpes viruses appears no different from healthy controls, there is some evidence of viral persistence and inadequate containment of viral replication. The ability of certain herpes viruses to impair the development of T cell memory may explain this viral persistence and the continuation of symptoms. New therapies based on this understanding are more likely to produce benefit than current methods.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2012 Jan;26(1):24-31. doi: 10.1016/j.bbi.2011.06.016. Epub 2011 Jul 2. https://www.ncbi.nlm.nih.gov/pubmed/21756995

 

Evidence for enteroviral persistence in humans

Abstract:

We have sought evidence of enteroviral persistence in humans. Eight individuals with chronic fatigue syndrome (CFS) were positive for enteroviral sequences, detected by PCR in two serum samples taken at least 5 months apart. The nucleotide sequence of the 5′ non-translated region (bases 174-423) was determined for each amplicon.

Four individuals had virtually identical nucleotide sequences ( > 97%) in both samples. The sequence pairs also each had a unique shared pattern indicating that the virus had persisted. In one individual (HO), it was clear that there had been infection with two different enteroviruses.

In the remaining three individuals, the lack of unique shared features suggested that re-infection had occurred, rather than persistence. With the exception of HO, the sequences fell into a subgroup that is related to the Coxsackie B-like viruses.

 

Source: Galbraith DN, Nairn C, Clements GB. Evidence for enteroviral persistence in humans. J Gen Virol. 1997 Feb;78 ( Pt 2):307-12. http://www.ncbi.nlm.nih.gov/pubmed/9018051