Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

Gray, Paul; Bartlett, Adam W.; Tangye, Stuart G.

doi:10.1002/cti2.1365

Cited by 9 publications

(7 citation statements)

References 109 publications

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“…8 These genes induce overproduction of pro-inflammatory cytokines, such as type I interferons that cause immunological dysregulation. 45 This suggests that the search for potential antiviral drugs should also consider targets with anti-inflammatory pathways. 46 We also meta-analysed the SNP-h 2 (proportion of phenotypic variance explained by genetic factors) of COVID-19 susceptibility and severity.…”

Section: Discussionmentioning

confidence: 99%

“…A study reveals that high expression of OAS1 and TYK2 is associated with life‐threatening disease 8 . These genes induce overproduction of pro‐inflammatory cytokines, such as type I interferons that cause immunological dysregulation 45 . This suggests that the search for potential antiviral drugs should also consider targets with anti‐inflammatory pathways 46 …”

Section: Discussionmentioning

confidence: 99%

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Host genetic determinants of COVID‐19 susceptibility and severity: A systematic review and meta‐analysis

Eshetie

Jullian

Benyamin

et al. 2023

Reviews in Medical Virology

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Genome‐wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with susceptibility and severity of coronavirus disease 2019 (COVID‐19). However, identified SNPs are inconsistent across studies, and there is no compelling consensus that COVID‐19 status is determined by genetic factors. Here, we conducted a systematic review and meta‐analysis to determine the effect of genetic factors on COVID‐19. A random‐effect meta‐analysis was performed to estimate pooled odds ratios (ORs) of SNP effects, and SNP‐based heritability (SNP‐h2) of COVID‐19. The analyses were performed using meta‐R package, and Stata version 17. The meta‐analysis included a total of 96,817 COVID‐19 cases and 6,414,916 negative controls. The meta‐analysis showed that a cluster of highly correlated 9 SNPs (R2 > 0.9) at 3p21.31 gene locus covering LZTFL1 and SLC6A20 genes was significantly associated with COVID‐19 severity, with a pooled OR of 1.8 [1.5–2.0]. Meanwhile, another 3 SNPs (rs2531743‐G, rs2271616‐T, and rs73062389‐A) within the locus was associated with COVID‐19 susceptibility, with pooled estimates of 0.95 [0.93–0.96], 1.23 [1.19–1.27] and 1.15 [1.13–1.17], respectively. Interestingly, SNPs associated with susceptibility and SNPs associated with severity in this locus are in linkage equilibrium (R2 < 0.026). The SNP‐h2 on the liability scale for severity and susceptibility was estimated at 7.6% (Se = 3.2%) and 4.6% (Se = 1.5%), respectively. Genetic factors contribute to COVID‐19 susceptibility and severity. In the 3p21.31 locus, SNPs that are associated with susceptibility are not in linkage disequilibrium (LD) with SNPs that are associated with severity, indicating within‐locus heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Host genetic determinants of COVID‐19 susceptibility and severity: A systematic review and meta‐analysis

Eshetie

Jullian

Benyamin

et al. 2023

Reviews in Medical Virology

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“…The cytokine IFN-ω is secreted by virus-infected leukocytes as a major component of human leukocyte interferon [ 93 ]. It is also detected in the serum of patients with severe coronavirus disease 2019 (COVID-19) [ 94 ]. These two proteins were produced under the control of the same promoter, GAL1 , in the EGFP-displaying yeast [ 91 ].…”

Section: Applications As a Cell Sensor For Biosensing And Biomonitoringmentioning

confidence: 99%

Progress of Molecular Display Technology Using Saccharomyces cerevisiae to Achieve Sustainable Development Goals

Shibasaki

Ueda

2023

Microorganisms

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In the long history of microorganism use, yeasts have been developed as hosts for producing biologically active compounds or for conventional fermentation. Since the introduction of genetic engineering, recombinant proteins have been designed and produced using yeast or bacterial cells. Yeasts have the unique property of expressing genes derived from both prokaryotes and eukaryotes. Saccharomyces cerevisiae is one of the well-studied yeasts in genetic engineering. Recently, molecular display technology, which involves a protein-producing system on the yeast cell surface, has been established. Using this technology, designed proteins can be displayed on the cell surface, and novel abilities are endowed to the host yeast strain. This review summarizes various molecular yeast display technologies and their principles and applications. Moreover, S. cerevisiae laboratory strains generated using molecular display technology for sustainable development are described. Each application of a molecular displayed yeast cell is also associated with the corresponding Sustainable Development Goals of the United Nations.

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“…SARS-CoV-2 VOCs (namely Alpha, Beta, Gamma, Delta, and Omicron) are reported to exhibit increased interferon resistance as compared to the wild -type suggesting evasion of innate immunity is a driving force for SARS-CoV-2 evolution [23, 24]. Furthermore, inborn variation in immunity-associated genes is reported to trigger susceptibility to COVID-19 [25, 26]. For example, rare variants in the Toll-like receptor 7 gene have been associated with increased severity and susceptibility of the COVID-19 [12].…”

Section: Introductionmentioning

confidence: 99%

“…Innate immune suppression is known as one of the key characteristics of infections by SARS-CoV-2 and its VOCs. SARS-CoV-2 VOCs (namely Alpha, Beta, Gamma, Delta, and Omicron) are reported to exhibit increased interferon resistance as compared to the wild -type suggesting evasion of innate immunity is a driving force for SARS-CoV-2 evolution [23,24]. Furthermore, inborn variation in immunity-associated genes is reported to trigger susceptibility to COVID-19 [25,26].…”

Section: Introductionmentioning

confidence: 99%

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Waman,

Ashford,

Lam

et al. 2023

Preprint

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The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19.In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and its human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed impact of missense variants occurring in the protein-protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities to SARS-CoV-2 proteins, using 3D-complexes.We predicted a total of 26 affinity-enhancing variants from 14 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, RAE1, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed.Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.

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Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

Cited by 9 publications

References 109 publications

Host genetic determinants of COVID‐19 susceptibility and severity: A systematic review and meta‐analysis

Host genetic determinants of COVID‐19 susceptibility and severity: A systematic review and meta‐analysis

Progress of Molecular Display Technology Using Saccharomyces cerevisiae to Achieve Sustainable Development Goals

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

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