Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation

Wu, Haibo; He, Peiqi; Ren, Yong; Xiao, Shiqi; Wang, Wei; Liu, Zhenbang; Li, Heng; Wang, Zhe; Zhang, Dingyu; Cai, Jun; Zhou, Xiangdong; Jiang, Dongpo; Fei, Xiaochun; Zhao, Lei; Zhang, Heng; Liu, Zhenhua; Chen, Rong; Li, Weiqing; Wang, Chaofu; Zhang, Shuyang; Qin, Jiwei; Nashan, Björn; Sun, Cheng

doi:10.1038/s41467-021-27723-5

Cited by 17 publications

(22 citation statements)

References 50 publications

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“…Additionally, the levels of LAG-3 and PD-1 on CD4 + T cells, and LAG-3 and TIM-3 on CD8 + T cells were elevated at the 6-7 month time point. The expression of negative immune checkpoint molecules TIM-3 and PD-1 mediates immunosuppression in lung, and was found to be a hallmark of severe COVID-19, particularly in men [104]. Besides the induction of the negative immune checkpoint molecules, chronic stimulation can give rise to CD57 + exhausted T cells.…”

Section: Discussionmentioning

confidence: 99%

Long-term T cell perturbations and waning antibody levels in individuals needing hospitalization for COVID-19

Govender

Hopkins

Göransson

et al. 2022

Preprint

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COVID-19 is being extensively studied, and much remains unknown regarding the long-term consequences of the disease on immune cells. The different arms of the immune system are interlinked, with humoral responses and the production of high-affinity antibodies being largely dependent on T cell immunity. Here, we longitudinally explored the effect COVID-19 has on T cell populations and the virus-specific T cells, as well as neutralizing antibody responses, for 6-7 months following hospitalization. The CD8+ TEMRA and exhausted CD57+CD8+ T cells were markedly affected with elevated levels that lasted long into convalescence. Further, markers associated with T-cell activation were upregulated at the inclusion, and in the case of CD69+CD4+ T cells this lasted all through the study duration. The levels of T cells expressing negative immune checkpoint molecules were increased in COVID-19 patients and sustained for a prolonged duration following recovery. Within 2-3 weeks after symptom onset, all COVID-19 patients developed anti-nucleocapsid IgG and spike-neutralizing IgG as well as SARS-CoV-2-specific T cell responses. In addition, we found alterations in follicular T helper (TFH) cell populations, such as enhanced TFH-TH2 following recovery from COVID-19. Our study revealed significant and long-term alterations in T cell populations and key events associated with COVID-19 pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Long-term T cell perturbations and waning antibody levels in individuals needing hospitalization for COVID-19

Govender

Hopkins

Göransson

et al. 2022

Preprint

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“…Therefore, whether the exhausted CD8+ T cell phenotype is primarily due to exhaustion or secondary to hyperactivation remains unclear. To this end, a recent study compared the immune landscape in 11 postmortem COVID-19 lungs versus three non-COVID-19 lungs ( 234 ). An immunosuppressive phenotype was detected, as evidenced by greater TIM-3 and PD-1 in COVID-19 lungs.…”

Section: Adaptive Immune Response Against Sars-cov-2mentioning

confidence: 99%

“…The immunosuppression also selectively affected T-cells. Men exhibit greater magnitudes of immunosuppression than women, and a positive correlation between TIM-3 expression and aging exists in men but not women ( 234 ), which perhaps contributes to males being more vulnerable to severe disease than females.…”

Section: Adaptive Immune Response Against Sars-cov-2mentioning

confidence: 99%

“…However, blocking immune checkpoints may conversely augment dysfunctional T-cell responses in severe patients and, in turn, mediate immunopathology. Indeed, cancer patients receiving these therapies develop severe COVID-19, but whether checkpoint inhibiting therapies or the generally increased vulnerability of cancer patients to severe infections explain this remains unknown ( 234 ). Therefore, more extensive studies on patients not suffering from comorbidities, which independently increase the likelihood of severe disease, are needed.…”

Section: Adaptive Immune Response Against Sars-cov-2mentioning

confidence: 99%

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Mechanistic Insights Into the Immune Pathophysiology of COVID-19; An In-Depth Review

Shafqat

Salameh

et al. 2022

Front. Immunol.

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which causes coronavirus-19 (COVID-19), has caused significant morbidity and mortality globally. In addition to the respiratory manifestations seen in severe cases, multi-organ pathologies also occur, making management a much-debated issue. In addition, the emergence of new variants can potentially render vaccines with a relatively limited utility. Many investigators have attempted to elucidate the precise pathophysiological mechanisms causing COVID-19 respiratory and systemic disease. Spillover of lung-derived cytokines causing a cytokine storm is considered the cause of systemic disease. However, recent studies have provided contradictory evidence, whereby the extent of cytokine storm is insufficient to cause severe illness. These issues are highly relevant, as management approaches considering COVID-19 a classic form of acute respiratory distress syndrome with a cytokine storm could translate to unfounded clinical decisions, detrimental to patient trajectory. Additionally, the precise immune cell signatures that characterize disease of varying severity remain contentious. We provide an up-to-date review on the immune dysregulation caused by COVID-19 and highlight pertinent discussions in the scientific community. The response from the scientific community has been unprecedented regarding the development of highly effective vaccines and cutting-edge research on novel therapies. We hope that this review furthers the conversations held by scientists and informs the aims of future research projects, which will potentially further our understanding of COVID-19 and its immune pathogenesis.

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“…ACE2 is highly expressed in the lung and binds to the spike protein on the SARS-CoV-2 virus, creating a biological vulnerability to infection [ 17 , 18 , 19 ••]. Higher levels of ACE2 expression are correlated with greater susceptibility to SARS-CoV-2 infection and viral loads [ 15 ]. Following attachment to the ACE2 receptor, the host protein transmembrane serine protease 2 (TMPRSS2) activates the spike protein of SARS-CoV-2, facilitating membrane fusion that allows the virus to spread in lung tissue [ 20 ].…”

Section: Summary Of Immune Pathways Involved In Covid-19 Infection Pr...mentioning

confidence: 99%

Epigenetics at the Intersection of COVID-19 Risk and Environmental Chemical Exposures

Bulka

Enggasser

Fry

2022

Curr Envir Health Rpt

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Purpose of Review Several environmental contaminants have been implicated as contributors to COVID-19 susceptibility and severity. Immunomodulation and epigenetic regulation have been hypothesized as mediators of this relationship, but the precise underlying molecular mechanisms are not well-characterized. This review examines the evidence for epigenetic modification at the intersection of COVID-19 and environmental chemical exposures. Recent Findings Numerous environmental contaminants including air pollutants, toxic metal(loid)s, per- and polyfluorinated substances, and endocrine disrupting chemicals are hypothesized to increase susceptibility to the SARS-CoV-2 virus and the risk of severe COVID-19, but few studies currently exist. Drawing on evidence that many environmental chemicals alter the epigenetic regulation of key immunity genes and pathways, we discuss how exposures likely perturb host antiviral responses. Specific mechanisms vary by contaminant but include general immunomodulation as well as regulation of viral entry and recognition, inflammation, and immunologic memory pathways, among others. Summary Associations between environmental contaminants and COVID-19 are likely mediated, in part, by epigenetic regulation of key immune pathways involved in the host response to SARS-CoV-2.

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Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation

Cited by 17 publications

References 50 publications

Long-term T cell perturbations and waning antibody levels in individuals needing hospitalization for COVID-19

Long-term T cell perturbations and waning antibody levels in individuals needing hospitalization for COVID-19

Mechanistic Insights Into the Immune Pathophysiology of COVID-19; An In-Depth Review

Epigenetics at the Intersection of COVID-19 Risk and Environmental Chemical Exposures

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