Delayed bystander CD8 T cell activation, early immune pathology and persistent dysregulation characterise severe COVID-19

Bergamaschi, Laura; Mescia, Federica; Turner, Lorinda; Hanson, Aimee L.; Kotagiri, Prasanti; Dunmore, Benjamin J.; Ruffieux, Hélène; DeSa, Aloka; Huhn, Oisín; Morgan, Michael D.; Gerber, Pehuén Pereyra; Wills, Mark R.; Baker, Stephen; Nieto, Fernando J Calero; Döffinger, Rainer; Dougan, Gordon; Elmer, Anne; Goodfellow, Ian; Gupta, Ravindra; Hosmillo, Myra; Hunter, Kelvin; Kingston, Nathalie; Lehner, Paul J.; Matheson, Nicholas J; Nicholson, Jeremy K.; Petrunkina, A. M.; Richardson, Sylvia; Saunders, Caroline; Thaventhiran, James; Toonen, Erik J. M.; Weekes, Michael P.; CambridgeInstituteofTherapeuticImmunologyandInfectiousDisease-NationalInstituteofHealthResearch,; Göttgens, Berthold; Toshner, Mark; Hess, Christoph; Bradley, John R.; Lyons, Paul; Smith, Kenneth

doi:10.1101/2021.01.11.20248765

Cited by 11 publications

(19 citation statements)

References 89 publications

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“…Total serum IgM fell as disease severity increased, with many patients in groups C--E having IgM levels below the normal range, while IgG and IgA were less impacted (Figures 1c and S1a). Anti--SARS--CoV--2 spike antibodies rose over time in all severity groups, reaching highest titres in the more severe groups (Bergamaschi et al, 2021). BCR sequencing showed reduced somatic mutation in COVID--19 patients, most prominent in IgA and IgG1/2 (Figures 1d and S1b), consistent with previous reports (Nielsen et al, 2020).…”

Section: Persistent B Cell Dysregulation In Covid--19supporting

confidence: 89%

“…We compared absolute B cell subset numbers in COVID--19 patients to 45 healthy controls, including some previously reported data for comparison (Figure 1b) (Bergamaschi et al, 2021). In asymptomatic HCWs (group A) an often non--significant increase in most B cell subsets occurred, while in Group B mild and short--lived reductions in IgA and IgG memory and in marginal zone--like (MZL) B cells were seen.…”

Section: Persistent B Cell Dysregulation In Covid--19mentioning

confidence: 98%

“…SARS--CoV--2 PCR--positive subjects were recruited between 31 st March and 20 th July 2020 and divided into five categories according to peak clinical severity (Bergamaschi et al, 2021) (Figure 1a):…”

Section: Patient Cohortsmentioning

confidence: 99%

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The impact of hypoxia on B cells in COVID-19

Kotagiri

Mescia

Hanson

et al. 2021

Preprint

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Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This brought to mind the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. We demonstrated the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes we also observed in B cell VHL-deficient mice. This was corroborated by hypoxia-related transcriptional changes in COVID-19 patients, and by similar B cell abnormalities in mice kept in hypoxic conditions, including reduced marginal zone and germinal center B cells. Thus hypoxia might contribute to B cell pathology in COVID-19, and in other hypoxic states. Through this mechanism it may impact on COVID-19 outcome, and be remediable through early oxygen therapy.

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Section: Persistent B Cell Dysregulation In Covid--19supporting

confidence: 89%

Section: Persistent B Cell Dysregulation In Covid--19mentioning

confidence: 98%

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The impact of hypoxia on B cells in COVID-19

Kotagiri

Mescia

Hanson

et al. 2021

Preprint

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“…There are more studies following-up hospitalised than non-hospitalised COVID-19 patients, with the assumption that hospitalisation indicates severe disease in most settings [17][18][19] . The natural history and pathology in those acutely severely ill with COVID-19 may be different to those developing Long Covid, but certain inflammatory or immunological mechanisms may be shared 20 . The multisystem nature of the illness is a common feature.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of Long Covid: findings from a social media survey

Ziauddeen

Gurdasani

O’Hara³

et al. 2021

Preprint

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Many people are not recovering for months after being infected with SARS-CoV-2. Long Covid has emerged as a major public health concern that needs defining, quantifying, and describing. We aimed to explore the initial and ongoing symptoms of Long Covid following SARS-CoV-2 infection and describe its impact on daily life in people who were not admitted to hospital during the first two weeks of the illness. We co-produced a survey with people living with Long Covid. We collected the data through an online survey using convenience non-probability sampling, with the survey posted both specifically on Long Covid support groups and generally on social media. The criteria for inclusion were adults with lab-confirmed (PCR or antibody) or suspected COVID-19 managed in the community (non-hospitalised) in the first two weeks of illness. We used agglomerative hierarchical clustering to identify specific symptom clusters, and their demographic and functional correlates. We analysed data from 2550 participants with a median duration of illness of 7.7 months (interquartile range (IQR) 7.4-8.0). The mean age was 46.5 years (standard deviation 11 years) with 82.8% females and 79.9% of participants based in the UK. 89.5% described their health as good, very good or excellent before COVID-19. The most common initial symptoms that persisted were exhaustion, chest pressure/tightness, shortness of breath and headache. Cough, fever, and chills were common initial symptoms that became less prevalent later in the illness, whereas cognitive dysfunction and palpitations became more prevalent later in the illness. 26.5% reported lab-confirmation of infection. The biggest difference in ongoing symptoms between those who reported testing positive and those who did not was loss of smell/taste. Ongoing symptoms affected at least 3 organ systems in 83.5% of participants. Most participants described fluctuating (57.7%) or relapsing symptoms (17.6%). Physical activity, stress and sleep disturbance commonly triggered symptoms. A third (32%) reported they were unable to live alone without any assistance at six weeks from start of illness. 16.9% reported being unable to work solely due to COVID-19 illness. 66.4% reported taking time off sick (median of 60 days, IQR 20, 129). 37.0% reported loss of income due to illness, and 64.4% said they were unable to perform usual activities/duties. Acute systems clustered broadly into two groups: a majority cluster (n=2235, 88%) with cardiopulmonary predominant symptoms, and a minority cluster (n=305, 12%) with multisystem symptoms. Similarly, ongoing symptoms broadly clustered in two groups; a majority cluster (n=2243, 88.8%) exhibiting mainly cardiopulmonary, cognitive symptoms and exhaustion, and a minority cluster (n=283, 11.2%) exhibited more multisystem symptoms. Belonging to the more severe multisystem cluster was associated with more severe functional impact, lower income, younger age, being female, worse baseline health, and inadequate rest in the first two weeks of the illness, with no major differences in the cluster patterns when restricting analysis to the lab-confirmed subgroup. This is an exploratory survey of Long Covid characteristics. Whilst it is important to acknowledge that it is a non-representative population sample, it highlights the heterogeneity of persistent symptoms, and the significant functional impact of prolonged illness following confirmed or suspected SARS-CoV-2 infection. To study prevalence, predictors and prognosis, research is needed in a representative population sample using standardised case definitions (to include those not lab-confirmed in the first pandemic wave).

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“…immune proteins that target a person's own cells and organs, and causes autoimmune diseases such as Lupus [48]. For some patients that recovered from COVID-19, the immune profiled reverted back to normal, but for others researchers found many immune cells altered many months after recovery from COVID-19 when patients no longer test positive for the SARS-CoV-2 virus [49][50][51][52]. Liu et al [49]…”

Section: Figure Box Plot For 22 Types Of Immune Cells In (A) 5 Patients From the Sars-cov-2 Dataset And (B) Patients From The Nl63-cov-himentioning

confidence: 99%

Computational genomic analysis of the lung tissue microenvironment in COVID-19 patients

Bhuvaneshwar

Madhavan

Gusev

2021

Preprint

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The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has affected over 170 million people, and caused over 3.5 million deaths throughout the world as of May 2021. Although over 150 million people around the world have recovered from this disease, the long term effects of the disease are still under study. A year after the start of the pandemic, data from COVID-19 recovered patients shows multiple organs affected with a broad spectrum of manifestations. Long term effects of SARS-CoV-2 infection includes fatigue, chest pain, cellular damage, and robust innate immune response with inflammatory cytokine production. More clinical studies and trials are needed to not only document, but also to understand the factors that predispose certain people to the long term side effects of his infection. In this manuscript, our goal was to explore the multidimensional landscape of infected lung tissue microenvironment to better understand complex interactions between SARS-CoV-2 viral infection , immune response and the lungs microbiome of COVID-19 patients. Each sample was analyzed with several machine learning tools allowing simultaneous detection and quantification of viral RNA amount at genome and gene level; human gene expression and fractions of major types of immune cells, as well as metagenomic analysis of bacterial and viral abundance. To contrast and compare specific viral response to SARS-COV-2 we have analyzed deep sequencing data from additional cohort of patients infected with NL63 strain of corona virus. Correlation analysis of three types of measurements i.e. fraction of viral RNA, Human RNA and bacterial RNA (metagenomic analysis), showed significant correlation between viral load as well as level of specific viral gene expression with the fractions of immune cells present in lung lavage as well as with abundance of major fractions of lung microbiome in COVID-19 patients. Our exploratory study has provided novel insights into complex regulatory signaling interactions and correlative patterns between the viral infection, inhibition of innate and adaptive immune response as well as microbiome landscape of the lung tissue. These initial findings could provide better understanding of the diverse dynamics of immune response and the side effects of the SARS-CoV-2 infection.

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Delayed bystander CD8 T cell activation, early immune pathology and persistent dysregulation characterise severe COVID-19

Cited by 11 publications

References 89 publications

The impact of hypoxia on B cells in COVID-19

The impact of hypoxia on B cells in COVID-19

Characteristics of Long Covid: findings from a social media survey

Computational genomic analysis of the lung tissue microenvironment in COVID-19 patients

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