Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity

Zhang, Sai; Cooper‐Knock, Johnathan; Weimer, Annika K.; Shi, Minyi; Kozhaya, Lina; Unutmaz, Derya; Harvey, Calum; Julian, Thomas; Furini, Simone; Frullanti, Elisa; Fava, Francesca; Renieri, Alessandra; Gao, Peng; Shen, Xiaotao; Timpanaro, Ilia Sarah; Kenna, Kevin P.; Baillie, J Kenneth; Davis, Mark M.; Tsao, Philip S.; Snyder, M

doi:10.1016/j.cels.2022.05.007

Cited by 21 publications

(17 citation statements)

References 102 publications

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“… 6 A recently published genome‐wide association study localized the genetic risk for fatal COVID‐19 in particular to CD56 bright NK cells. 3 Additional ex vivo studies demonstrated that arming and activation of CD56 bright cells occurs especially in severely diseased COVID‐19 patients. 13 , 14 Other studies demonstrated that the CD56 bright ‐derived IFN‐γ, TNF‐α, GM‐CSF and IL‐13 levels are highly elevated in the serum of severely ill COVID‐19 patients, and may contribute to the disadvantageous immunopathogenesis, leading to a severe course of COVID‐19.…”

Section: Discussionmentioning

confidence: 99%

“…CD56 bright NK cells are a NK cell subset, which releases high‐levels of pro‐inflammatory cytokines 6 . A recently published genome‐wide association study localized the genetic risk for fatal COVID‐19 in particular to CD56 bright NK cells 3 . Additional ex vivo studies demonstrated that arming and activation of CD56 bright cells occurs especially in severely diseased COVID‐19 patients 13,14 .…”

Section: Discussionmentioning

confidence: 99%

“… 2 Importantly, among the host genes, which were recently associated with severe COVID‐19, the majority were associated with CD56 bright natural killer (NK) cell responses. 3 …”

Section: Introductionmentioning

confidence: 99%

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The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

Vietzen

Furlano

Traugott³

et al. 2022

Journal of Medical Virology

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The severity of COVID‐19 is associated with individual genetic host factors. Among these, genetic polymorphisms affecting natural killer (NK) cell responses, as variations in the HLA‐E‐ (HLA‐E*0101/0103), FcγRIIIa‐ (FcγRIIIa‐158‐F/V), and NKG2C‐ (KLRC2wt/del) receptor, were associated with severe COVID‐19. Recently, the rs9916629‐C/T genetic polymorphism was identified that indirectly shape the human NK cell repertoire towards highly pro‐inflammatory CD56bright NK cells. We investigated whether the rs9916629‐C/T variants alone and in comparison to the other risk factors are associated with a fatal course of COVID‐19. We included 1042 hospitalized surviving and 159 nonsurviving COVID‐19 patients as well as 1000 healthy controls. rs9916629‐C/T variants were genotyped by TaqMan assays and were compared between the groups. The patients' age, comorbidities, HLA‐E*0101/0103, FcγRIIIa‐158‐F/V, and KLRC2wt/del variants were also determined. The presence of the rs9916629‐C allele was a risk factor for severe and fatal COVID‐19 (p < 0.0001), independent of the patients' age or comorbidities. Fatal COVID‐19 was more frequent in younger patients (<69.85 years) carrying the FcγRIIIa‐158‐V/V (p < 0.006) and in older patients expressing the KLRC2del variant (p < 0.003). Thus, patients with the rs9916629‐C allele have a significantly increased risk for fatal COVID‐19 and identification of the genetic variants may be used as prognostic marker for hospitalized COVID‐19 patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

Vietzen

Furlano

Traugott³

et al. 2022

Journal of Medical Virology

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“…New research has helped identify over 1000 genes related to a severe course of COVID-19. Moreover, it has been shown that severe COVID-19 is highly associated with a poor reaction of two immune cell types: natural killer (NK) cells and T lymphocytes (the ‘CD56 bright’ subtype) [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Neurological consequences of COVID-19

Brola

Wilski²

2022

Pharmacol. Rep

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In December 2019, cases of pneumonia caused by infection with the previously unknown severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to coronavirus disease 2019 (COVID-19), were identified. Typical manifestations of COVID-19 are fever, cough, fatigue and dyspnoea. Initially, it was thought that the mechanism of action of SARS-CoV-2 was only associated with respiratory tract invasion, but it was later revealed that the infection might involve many other organs and systems, including the central and peripheral nervous systems. Neurological complications associated with SARS-CoV-2 infection include encephalopathy, encephalitis, meningitis, acute disseminated encephalomyelitis (ADEM), ischaemic and haemorrhagic stroke and cerebral venous sinus thrombosis. In cases of peripheral nervous system involvement, smell and taste disorders, myopathy or the signs and symptoms of Guillain‒Barré syndrome are observed. The most common early neurological complications, particularly during the first year of the epidemic, were anosmia and taste disorders, which, according to some studies, occurred in over 80 percent of patients with COVID-19. The proportion of patients with serious neurological manifestations was small compared to the global number of patients, but the numbers of SARS-CoV-2 infections and critical patients increased substantially. The experience from 2 years of the pandemic has shown that approximately 13% of infected patients suffer from severe neurological complications. The relationship between SARS-CoV-2 and the nervous system is not only a cause of neurological complications in previously healthy individuals but also directly and indirectly affects the courses of many nervous system diseases.

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“…Severe infection is thought to result from a combination of uncontrolled viral replication and a late hyperinflammatory response leading to acute respiratory distress syndrome (Brodin, 2021). As a result, current therapeutic approaches seek to either boost host immunity (e.g., vaccines) (Olliaro et al, 2021;Zhang et al, 2022), reduce viral replication (e.g., molnupiravir [Jayk Bernal et al, 2021]), or reduce hyperinflammation (e.g., dexamethasone [RECOVERY Collaborative Group et al, 2021]). Very few strategies have sought to modify a host protein which interacts with the virus: an exception is camostat, a TMPRSS2 inhibitor, for which there is no good evidence of effectiveness (Gunst et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

et al. 2022

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New therapeutic targets are a valuable resource for treatment of SARS-CoV-2 viral infection. Genome-wide association studies have identified risk loci associated with COVID-19, but many loci are associated with comorbidities and are not specific to host–virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of the 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins. Aggregating COVID-19 genome-wide association studies statistics for gene-specific eQTLs revealed an association between increased expression ofEXOSC2and higher risk of clinical COVID-19. EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. EXOSC2 is a component of the RNA exosome, and here, LC-MS/MS analysis of protein pulldowns demonstrated interaction between the SARS-CoV-2 RNA polymerase and most of the human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations withinEXOSC2in Calu-3 cells reduced EXOSC2 protein expression and impeded SARS-CoV-2 replication without impacting cellular viability. Targeted depletion of EXOSC2 may be a safe and effective strategy to protect against clinical COVID-19.

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Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity

Cited by 21 publications

References 102 publications

The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

Neurological consequences of COVID-19

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

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