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Single cell susceptibility to SARS-CoV-2 infection is driven by variable cell states [scRNA-Seq]

ABSTRACT: The ability of a virus to infect a cell type is partly determined by host factors required for the viral life cycle. However, not every cell of a given type is equally susceptible, suggesting that our knowledge of the full spectrum of factors that promote infection is incomplete. Profiling the susceptible subsets of cells could reveal additional host factors, but viral infection dramatically alters the state of the cell, obscuring the state of these cells prior to infection. We used single-cell clone tracing to retrospectively identify cells that were highly susceptible to infection with SARS-CoV-2. Our approach revealed candidate factors playing roles in viral entry and regulation of the infectable cell state itself. Patient samples revealed heterogeneous expression of these factors in vivo, with heightened expression in particular inflammatory pathologies. Thus, variable expression of intrinsic cell states is a major determinant of whether individual cells can be infected by SARS-CoV-2.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236941 | GEO | 2023/07/12

REPOSITORIES: GEO

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Single cell susceptibility to SARS-CoV-2 infection is driven by variable cell states [bulkRNA-Seq]

Project description:The ability of a virus to infect a cell type is partly determined by host factors required for the viral life cycle. However, not every cell of a given type is equally susceptible, suggesting that our knowledge of the full spectrum of factors that promote infection is incomplete. Profiling the susceptible subsets of cells could reveal additional host factors, but viral infection dramatically alters the state of the cell, obscuring the state of these cells prior to infection. We used single-cell clone tracing to retrospectively identify cells that were highly susceptible to infection with SARS-CoV-2. Our approach revealed candidate factors playing roles in viral entry and regulation of the infectable cell state itself. Patient samples revealed heterogeneous expression of these factors in vivo, with heightened expression in particular inflammatory pathologies. Thus, variable expression of intrinsic cell states is a major determinant of whether individual cells can be infected by SARS-CoV-2.

2023-07-12 | GSE236939 | GEO

Diferential expression analyses PLAC8 defective cells

Project description:SARS-CoV-2 pandemic has caused a dramatic health, social and economic crisis worldwide. To better understand the host-virus interactions and identify potentially targetable host factors, we have conducted CRISPR-Cas9 genetic screens using SARS-CoV-2 pseudotyped lentiviruses on human lung cancer cells. Our results recapitulate many findings from previous screens that used full SARS-CoV-2 viruses, but also unveil two novel critical host factors: SPNS1 and PLAC8. Functional experiments with full SARS-CoV-2 viruses have confirmed that loss-of-function of these genes impairs viral entry. Importantly, we have found that PLAC8 is a key limiting host factor whose overexpression boosts viral infection in eight different human lung cancer cell lines. Using single-cell RNA-Seq data analyses, we demonstrate that PLAC8 is highly expressed in ciliated and secretory cells from the respiratory tract and in gut enterocytes, cell types that are highly susceptible to SARS-CoV-2 infection. Finally, proteomics and cell biology studies suggest that SPNS1 and PLAC8 affect viral entry through regulation of autophagy and lysosomal function.

2022-09-06 | PXD036334 | Pride

Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

Project description:SARS-CoV-2 depends on host cell components for replication, therefore the identification of virus-host dependencies offers an effective way to elucidate mechanisms involved in viral infection. Such host factors may be necessary for infection and replication of SARS-CoV-2 and, if druggable, presents an attractive strategy for anti-viral therapy. We performed genome-wide CRISPR knockout screens in Vero E6 cells and 4 human cell lines including Calu-3, Caco-2, Hek293 and Huh7 to identify genetic regulators of SARS-CoV-2 infection. Our findings identified only ACE2, the cognate SARS-CoV-2 entry receptor, as a common host dependency factor across all cell lines, while all other host genes identified were cell line-specific, including known factors TMPRSS2 and CTSL. Several of the discovered host-dependency factors converged on pathways involved in cell signalling, lipid metabolism, immune pathways and chromatin modulation. Notably, chromatin modulator genes KMT2C and KDM6A in Calu-3 cells had the strongest impact in preventing SARS-CoV-2 infection when perturbed. Overall, the network of host factors that have been identified will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate the development of host-directed therapies.

2022-06-22 | GSE178699 | GEO

SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition

Project description:Viruses hijack host cell metabolism to acquire the building blocks required for viral replication. Understanding how SARS-CoV-2 alters host cell metabolism could lead to potential treatments for COVID-19, the disease caused by SARS-CoV-2 infection. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface cultures and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces host cell oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes in host cell metabolism, we show that SARS-CoV-2 increases activity of mTORC1, a master regulator of anabolic metabolism, in cell lines and patient lung stem cell-derived airway epithelial cells. We also show evidence of mTORC1 activation in COVID-19 patient lung tissue. Notably, mTORC1 inhibitors reduce viral replication in kidney epithelial cells and patient-derived lung stem cell cultures. This suggests that targeting mTORC1 could be a useful antiviral strategy for SARS-CoV-2 and treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.

2021-02-19 | ST001709 | MetabolomicsWorkbench

The SARS-CoV-2 RNA-protein interactome in infected human cells

Project description:Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry (RAP-MS), we identify up to 104 human proteins that directly and specifically bind to SARS-CoV-2 RNAs in infected human cells. We integrate the SARS-CoV-2 RNA interactome with proteome abundance changes induced by viral infection and link interactome proteins to cellular pathways relevant to SARS-CoV-2 infections. We demonstrate by genetic perturbation that CNBP and LARP1, two of the most strongly enriched viral RNA binders, restrict SARS-CoV-2 replication in infected cells and provide a global map of their direct RNA contact sites. Pharmacological inhibition of three other RNA interactome members, PPIA, ATP1A1, and the ARP2/3 complex, reduces viral replication in two human cell lines. The identification of host dependency factors and defence strategies as presented in this work will improve the design of targeted therapeutics against SARS-CoV-2.

2020-12-01 | GSE154430 | GEO

Attenuation of SARS-CoV-2 Infection by Losartan in Human Kidney Organoids

Project description:COVID-19 associated acute kidney injury (COVID-AKI) is a common complication of SARS-CoV-2 infection in hospitalized patients. It is unclear how susceptible human kidneys are to direct SARS-CoV-2 infection and whether pharmacologic manipulation of the renin-angiotensin II signaling (RAS) pathway modulates this susceptibility. Using induced pluripotent stem cell derived kidney organoids, SARS-CoV-1, SARS-CoV-2 and MERS-CoV tropism, defined by the paired expression of a host receptor (ACE2, NRP1 or DPP4) and protease (TMPRSS2, TMPRSS4, FURIN, CTSB or CTSL), was identified primarily amongst proximal tubule cells. Losartan, an angiotensin II receptor blocker being tested in COVID-19 patients, inhibited angiotensin II mediated internalization of ACE2, upregulated interferon stimulated genes (IFITM1 and BST2) known to restrict viral entry, and attenuated the infection of proximal tubule cells by SARS-CoV-2. Our work highlights the susceptibility of proximal tubule cells to SARS-CoV-2 and reveals a putative protective role for RAS inhibitors during SARS-CoV-2 infection.

2022-01-23 | GSE149687 | GEO

Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control SARS-CoV-2 infection remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively which cellular and viral RBPs are involved in SARS-CoV-2 infection. We reveal that the cellular RNA-bound proteome is remodelled upon SARS-CoV-2 infection, having widespread effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

2021-05-29 | GSE171382 | GEO

Systematic functional interrogation of SARS-CoV-2 host factors using Perturb-seq

Project description:Numerous host factors of SARS-CoV-2 have been identified by screening approaches, but delineating their molecular roles during infection and whether they can be targeted for antiviral intervention remains a challenge. Here we use Perturb-seq, a single-cell CRISPR screening approach, to investigate how CRISPR interference of host factors changes the course of SARS-CoV-2 infection and the host response in human lung epithelial cells. Our data reveal two classes of host factors with pronounced phenotypes: factors required for the response to interferon, and factors required for entry or early infection, respectively. Among the latter, we have characterized the NF-κB inhibitor IκBα (NFKBIA), as well as the translation factors EIF4E2 and EIF4H as strong host dependency factors acting early in infection. Overall, our study provides high-throughput functional validation of host factors of SARS-CoV-2 and their roles during viral infection in both infected and uninfected bystander cells.

2022-07-26 | GSE208240 | GEO

Comparative Pathogenesis of Three Human and Zoonotic SARS-CoV Strains in Cynomolgus Macaques

Project description:The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. Host responses to the three SARS-CoV strains were similar and only apparent early during infection with the majority of genes associated with interferon signalling pathways.This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use 4 strains, time course, lungs

2011-08-31 | E-GEOD-23955 | biostudies-arrayexpress

Variant specific global loss of cellular m6A RNA methylation during SARS-CoV-2 infection

Project description:COVID-19 pandemic caused by SARS-CoV-2 is far from getting over because of the emergence of different SARS-CoV-2 variants even though vaccination against SARS-CoV-2 is ongoing. Variant specific mechanistic understanding of host-viral interaction will be required to design novel anti-viral therapeutics. N6-methyladenosine modification (m6A) which is one of the abundant cellular RNA modifications regulates key processes in RNA metabolism during stress response. We observed different SARS-CoV-2 variants during infection causes global loss of m6A in cellular RNA whereas m6A modification was detected abundantly in viral RNA. The loss of m6A in cellular RNAs was more drastic in B.1 and B1.1.7 strains and the main m6A methyltransferase METTL3 shows cytoplasmic localization post-infection. In B1.351 variant effect on METTL3 localization and loss of m6A was less pronounced compared to B.1 and B1.1.7 variants. Gene expression profile suggested changes in RNA catabolism-related pathways including key genes related to m6A readers and erasers during SARS-CoV-2 infection. Genes with m6A peaks were more susceptible to down-regulation during viral infection. Inhibition of export protein XPO1 during infection results in restoration of METTL3 nuclear localization and reduction in viral infection in cell culture suggesting XPO1 inhibition could be an effective therapeutic option for SARS-CoV-2.

2023-02-07 | GSE188477 | GEO

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