Common genetic variation in humans impacts<i>in vitro</i>susceptibility to SARS-CoV-2 infection

Dobrindt, Kristina; Hoagland, Daisy A.; Seah, Carina; Kassim, Bibi; O'Shea, Callan; Iskhakova, Marina; Fernando, Michael B.; Deans, P.J. Michael; Powell, Samuel K.; Javidfar, Ben; Murphy, Aleta; Peter, Cyril J.; Møeller, Rasmus; García, Meilín Fernández; Kimura, Masaki; Iwasawa, Kentaro; Crary, John F.; Kotton, Darrell N.; Takebe, Takanori; Huckins, Laura; tenOever, Benjamin R.; Akbarian, Schahram; Brennand, Kristen J.

doi:10.1101/2020.09.20.300574

Cited by 11 publications

(9 citation statements)

References 113 publications

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“…The likely causal TMPRSS2 eQTL variant rs35074065 is predicted to disrupt STAT and IRF binding, raising the possibility that STAT and/or IRF binding at this site may directly control TMPRSS2 gene expression. Further experimental follow-up studies will be needed to validate the effect of these variants on TF binding and TMPRSS2 expression, for example using electrophorectic mobility shift assays (EMSA), enhancer/promoter reporter assays, genome editing of in vitro models such as alveolar organoids ( Dobrindt et al, 2020 ; Jacob et al, 2017 ). It is interesting that multiple variants linked to TMPRSS2 were associated with pulmonary function or pulmonary disease medication use.…”

Section: Discussionmentioning

confidence: 99%

Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes

Wang

Chiou

Poirion

et al. 2020

eLife

154

173

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Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs from donors of ~30 weeks gestation,~3 years and ~30 years. We mapped candidate cis-regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene TMPRSS2 in alveolar type 2 cells, which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to SLC6A20, a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.

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Section: Discussionmentioning

confidence: 99%

Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes

Wang

Chiou

Poirion

et al. 2020

eLife

154

173

View full text Add to dashboard Cite

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“…Dobrindt et al (2020) obtained CRISPR‐edited Furin‐rs4702 (GG) in lung cells and neurons, and then they investigated the effects of this genetic variant on SARS‐CoV‐2 infection. rs4702 GG alveolospheres exhibited a decreased Furin expression and SARS‐CoV‐2 infection.…”

Section: Genetic Variants Of Cellular Proteasesmentioning

confidence: 99%

Genetic and epigenetic factors associated with increased severity of Covid‐19

Yildirim

Sahin

Yazar

et al. 2021

Cell Biology International

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Since December 2019, a new form of severe acute respiratory syndrome (SARS) from a novel strain of coronavirus (SARS coronavirus 2 [SARS‐CoV‐2]) has been spreading worldwide. The disease caused by SARS‐CoV‐2 was named Covid‐19 and declared as a pandemic by the World Health Organization in March 2020. Clinical symptoms of Covid‐19 range from common cold to more severe disease defined as pneumonia, hypoxia, and severe respiratory distress. In the next stage, disease can become more critical with respiratory failure, sepsis, septic shock, and/or multiorgan failure. Outcomes of Covid‐19 indicate large gaps between the male–female and the young–elder groups. Several theories have been proposed to explain variations, such as gender, age, comorbidity, and genetic factors. It is likely that mixture of genetic and nongenetic factors interplays between virus and host genetics and determines the severity of disease outcome. In this review, we aimed to summarize current literature in terms of potential host genetic and epigenetic factors that associated with increased severity of Covid‐19. Several studies indicated that the genetic variants of the SARS‐CoV‐2 entry mechanism‐related (angiotensin‐converting enzymes, transmembrane serine protease‐2, furin) and host innate immune response‐related genes (interferons [IFNs], interleukins, toll‐like receptors), and human leukocyte antigen, ABO, 3p21.31, and 9q34.2 loci are critical host determinants related to Covid‐19 severity. Epigenetic mechanisms also affect Covid‐19 outcomes by regulating IFN signaling, angiotensin‐converting enzyme‐2, and immunity‐related genes that particularly escape from X chromosome inactivation. Enhanced understanding of host genetic and epigenetic factors and viral interactions of SARS‐CoV‐2 is critical for improved prognostic tools and innovative therapeutics.

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“…In the brain, viruses encounter a variety of different cell types such as neurons, astrocytes and microglia. Investigations of CNS cell-type specific infection of SARS-CoV-2 have been inconsistent [16][17][18][19][20][21][22][23] . Most of studies have investigated virus replication by detection of viral RNA, but have not reported whether infectious progeny viruses are produced.…”

Section: Introductionmentioning

confidence: 99%

Replication kinetic, cell tropism and associated immune responses in SARS-CoV-2 and H5N1 virus infected human iPSC derived neural models

Bauer

Lendemeijer

Leijten

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a wide variety of neurological complications. Even though SARS-CoV-2 is rarely detected in the central nervous system (CNS) or cerebrospinal fluid, evidence is accumulating that SARS-CoV-2 might enter the CNS via the olfactory nerve. However, what happens after SARS-CoV-2 enters the CNS is poorly understood. Therefore, we investigated the replication kinetics, cell tropism, and associated immune responses of SARS-CoV-2 infection in different types of neural cultures derived from human induced pluripotent stem cells (hiPSCs). SARS-CoV-2 was compared to the neurotropic and highly pathogenic H5N1 influenza A virus. SARS-CoV-2 infected a minority of individual mature neurons, without subsequent virus replication and spread, despite ACE2, TMPRSS2 and NPR1 expression in all cultures. However, this sparse infection did result in the production of type-III-interferons and IL-8. In contrast, H5N1 virus replicated and spread very efficiently in all cell types in all cultures. Taken together, our findings support the hypothesis that neurological complications might result from local immune responses triggered by virus invasion, rather than abundant SARS-CoV-2 replication in the CNS.

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Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

Cited by 11 publications

References 113 publications

Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes

Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes

Genetic and epigenetic factors associated with increased severity of Covid‐19

Replication kinetic, cell tropism and associated immune responses in SARS-CoV-2 and H5N1 virus infected human iPSC derived neural models

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