The protein expression profile of ACE2 in human tissues

Hikmet, Feria; Méar, Loren; Edvinsson, Åsa; Micke, Patrick; Uhlén, Mathias; Lindskog, Cecilia

doi:10.15252/msb.20209610

Cited by 861 publications

(740 citation statements)

References 67 publications

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“…1D) to understand how air-liquid interface and co-culture may alter the expression of SARS-CoV-2 entry factors. In epithelial cells, ACE2 expression was low both in monoculture ( Fig S1A) and on-chip ( Fig 1D) consistent with transcriptomic 16,20 and proteomic analyses 21 of human tissue. Expression on-chip was five-fold lower than monoculture (Fig.…”

Section: Sars-cov-2 Infection Alters Relative Expression Of Viral Entsupporting

confidence: 75%

Rapid endothelial infection, endothelialitis and vascular damage characterise SARS-CoV-2 infection in a human lung-on-chip model

Thacker

Sharma

Dhar

et al. 2020

Preprint

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Background: Severe manifestations of COVID-19 include hypercoagulopathies and systemic endothelialitis. The underlying dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of immune cell-mediated cytokine storms is unknown. This is in part because in vitro infection models are typically monocultures of epithelial cells or fail to recapitulate vascular physiology. Methods: We establish a vascularised lung-on-chip infection model consisting of a co-culture of primary human alveolar epithelial (epithelial) cells and human lung microvascular endothelial (endothelial) cells, with the optional addition of CD14+ macrophages to the epithelial side. This model was used to study the dynamics of viral replication and host responses to a low dose infection of SARS-CoV-2 of the epithelial layer. Findings: SARS-CoV-2 inoculation does not lead to a productive amplification of infectious virions. However, both genomic and antisense viral RNA can be found in endothelial cells within 1-day post infection (dpi) and persist upnto 3 dpi. This generates an NF-KB-mediated inflammatory response typified by IL-6 secretion and signalling coupled with a weak antiviral interferon response, even in the absence of immune cells. Endothelial inflammation leads to a progressive loss of barrier integrity, a subset of cells also shows a transient hyperplasic phenotype. Administration of Tocilizumab slows the loss of barrier integrity but does not reduce the occurrence of the latter. Interpretation: Endothelial infection can occur through basolateral transmission from infected epithelial cells at the air-liquid interface. SARS-CoV-2 mediated inflammation occurs despite the lack of rapid viral replication and is transient in epithelial cells but persistent in endothelial cells. Infected endothelial cells might be a key source of circulating IL-6 in COVID-19 patients. Vascular damage occurs independently of immune-cell mediated cytokine storms, whose effect would only exacerbate the damage. Funding: Core support from EPFL.

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Section: Sars-cov-2 Infection Alters Relative Expression Of Viral Entsupporting

confidence: 75%

Rapid endothelial infection, endothelialitis and vascular damage characterise SARS-CoV-2 infection in a human lung-on-chip model

Thacker

Sharma

Dhar

et al. 2020

Preprint

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“…Our data underscore the possibility that the variation in the viral quasispecies that we see is not generated in the naso-or oropharynx, but rather more distally in the respiratory tract (lungs) or even in other tissues such as the gut. Reports on the comparative expression of the virus' cellular receptor ACE2 support the idea that those other tissues might be relevant sources of viral replication and, consequently, sites where diversity emerges [21,22].…”

Section: Discussionmentioning

confidence: 95%

SARS-CoV-2 genomic and quasispecies analyses in cancer patients reveal relaxed intrahost virus evolution

Siqueira

Goes

Alves

et al. 2020

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Numerous factors have been identified to influence susceptibility to SARS-CoV-2 infection and disease severity. Cancer patients are more prone to clinically evolve to more severe COVID-19 conditions, but the determinants of such a more severe outcome remain largely unknown. We have determined the full-length SARS-CoV-2 genomic sequences of cancer patients and healthcare workers (HCW; non-cancer controls) by deep sequencing and investigated the within-host viral quasispecies of each infection, quantifying intrahost genetic diversity. Naso- and oropharyngeal SARS-CoV-2+ swabs from 57 cancer patients and 14 healthcare workers (HCW) from the Brazilian Cancer Institute were collected in April–May 2020. Complete genome amplification using ARTIC network V3 multiplex primers was performed followed by next-generation sequencing. Assemblies were conducted in Geneious R11, where consensus sequences were extracted and intrahost single nucleotide variants (iSNVs) were identified. Maximum likelihood phylogenetic analysis was performed using PhyMLv.3.0 and lineages were classified using Pangolin and CoV-GLUE. Phylogenetic analysis showed that all but one strain belonged to clade B1.1. Four genetically linked mutations known as the globally dominant SARS-CoV-2 haplotype (C241T, C3037T, C14408T and A23403G) were found in the majority of consensus sequences. SNV signatures of previously characterized Brazilian genomes were also observed in most samples. Another 85 SNVs were found at a lower frequency (1.4-19.7%). Cancer patients displayed a significantly higher intrahost viral genetic diversity compared to HCW (p = 0.009). Intrahost genetic diversity in cancer patients was independent of SARS-CoV-2 Ct values, and was not associated with disease severity, use of corticosteroids, or use of antivirals, characteristics that could influence viral diversity. Such a feature may explain, at least in part, the more adverse outcomes to which cancer/COVID-19 patients experience.Author SummaryCancer patients are more prone to clinically evolve to more severe COVID-19 conditions, but the determinants of such a more severe outcome remain largely unknown. In this study, phylogenetic and variation analysis of SARS-CoV-2 genomes from cancer patients and non-cancer healthcare workers at the Brazilian National Cancer Institute were characterized by deep sequencing. Viral genomes showed signatures characteristic of Brazilian viruses, consistent with the hypothesis of local, community transmission rather than virus importation from abroad. Despite most genomes in patients and healthcare workers belonging to the same lineage, intrahost variability was higher in cancer patients when compared to non-cancer counterparts. The intrahost genomic diversity analysis presented in our study highlights the relaxed evolution of SARS-CoV-2 in a vulnerable population of cancer patients. The high number of minor variations can result in the selection of immune escape variants, resistance to potential drugs, and/or increased pathogenicity. The impact of this higher intrahost variability over time warrants further investigation.

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“…While the majority of hospitalized COVID-19 patients present with compromised airway function, a wide variety of effects on other organs have been noted. The primary SARS-CoV-2 receptor, angiotensin converting enzyme 2 (ACE2 59 ), is expressed in a wide variety of cell types 60 , including cardiomyocytes, cardiac pericytes, endothelial cells, fibroblasts, hepatocytes and multiple cell types in the kidney 61 , and kidney impairment 62,63 , cardiac injury 64 and liver dysfunction 65,66 are commonly observed in COVID-19 critical care patients. While the virus-related cytokine storm has been linked to organ damage 67 , a recent report also indicated that SARS-CoV-2 virus RNA was found in autopsied lung, pharynx, heart, liver, kidney, and brain 68 .…”

Section: Discussionmentioning

confidence: 99%

A SARS-CoV-2 – host proximity interactome

Samavarchi-Tehrani

Abdouni

Knight

et al. 2020

Preprint

131

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Viral replication is dependent on interactions between viral polypeptides and host proteins. Identifying virus-host protein interactions can thus uncover unique opportunities for interfering with the virus life cycle via novel drug compounds or drug repurposing. Importantly, many viral-host protein interactions take place at intracellular membranes and poorly soluble organelles, which are difficult to profile using classical biochemical purification approaches. Applying proximity-dependent biotinylation (BioID) with the fast-acting miniTurbo enzyme to 27 SARS-CoV-2 proteins in a lung adenocarcinoma cell line (A549), we detected 7810 proximity interactions (7382 of which are new for SARS-CoV-2) with 2242 host proteins (results available at covid19interactome.org). These results complement and dramatically expand upon recent affinity purification-based studies identifying stable host-virus protein complexes, and offer an unparalleled view of membrane-associated processes critical for viral production. Host cell organellar markers were also subjected to BioID in parallel, allowing us to propose modes of action for several viral proteins in the context of host proteome remodelling. In summary, our dataset identifies numerous high confidence proximity partners for SARS-CoV-2 viral proteins, and describes potential mechanisms for their effects on specific host cell functions.

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The protein expression profile of ACE2 in human tissues

Cited by 861 publications

References 67 publications

Rapid endothelial infection, endothelialitis and vascular damage characterise SARS-CoV-2 infection in a human lung-on-chip model

Rapid endothelial infection, endothelialitis and vascular damage characterise SARS-CoV-2 infection in a human lung-on-chip model

SARS-CoV-2 genomic and quasispecies analyses in cancer patients reveal relaxed intrahost virus evolution

A SARS-CoV-2 – host proximity interactome

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