Systemic analysis of tissue cells potentially vulnerable to SARS-CoV-2 infection by the protein-proofed single-cell RNA profiling of ACE2, TMPRSS2 and Furin proteases

Zhou, Lülin; Niu, Zubiao; Jiang, Xiaoyi; Zhang, Zhengrong; You, Zheng; Wang, Zhongyi; Zhu, Yichao; Gao, Lihua; Huang, Hongyan; Wang, Xiaoning; Sun, Qiang

doi:10.1101/2020.04.06.028522

Cited by 30 publications

(24 citation statements)

References 53 publications

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“…In fact, MERS-CoV was largely propagated by camel-to-human transmissions, as the virus was never able to fully adapt to optimal human-to-human transmission (8). expression information at the single cell level to rank the cells based on their susceptibility to the SARS-CoV-2 infection (20). Consistent with the sc RNA seq data, dual inhibition of the host cell cysteine and serine proteases impeded viral entry into the cell (21).…”

Section: Human Coronavirus (Hcov) Phylogenymentioning

confidence: 78%

Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection

Singh

Chen

Judy

et al. 2020

Preprint

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Lack of effective treatment strategy and vaccine makes SARS-CoV-2 infection a big threat to mankind. Analyzing the host transcriptional changes in response to virus infection will help delineate the biological processes impacted by the virus and will potentially facilitate drug development. Using RNA seq datasets of virus infected lung cell lines A549 (infected with either SARS-CoV-2 or Influenza A virus (IAV)) and Calu3 (infected with either SARS-CoV-2 or MERS-CoV), we present a detailed analysis of genes expression changes in response to each of these viral infections. Upregulation of the antiviral interferon signaling was observed with all three viral infections. However, upregulation of the cytokine/inflammatory processes, downregulation of mitochondrial organization and respiration processes, and perturbation in the autophagic processes were specifically observed in SARS-CoV-2 infected cells, which were absent in IAV infected cells. Upregulation of the inflammatory processes was concordant with the gene expression signature of COVID-19 lungs and with inflammatory symptoms observed in severe cases of COVID-19 patients. Coexpression networks analysis also facilitated the identification of protein-protein interaction (PPI) subnetworks of genes in the inflammation and mitochondrial processes that were either coordinately up or downregulated in SARS-CoV-2 infected cells, respectively. Comparing the expression of marker genes of lung cell types from single cell RNA seq data with expression profile of A549 cells revealed that they likely represent the lung epithelial lineage cells. The cellular processes uniquely perturbed in infected cells that were identified in this analysis likely delineates lung epithelial cells response to the SARS-CoV-2 infection. PathogenicityAs obligate parasites, the viruses, while evading the host cell immune response, should encode enough proteins to ensure replication, and spread, by relying on the host cell's machinery. These processes require an intricate series of interaction between the virus and host (9). While many of the elicited responses are common across pathogens, each virus also creates a unique transcriptional profile (10). Functional distinctions across viruses may arise due to distinct processes utilized by a virus for cellular entry, or for host immune system evasion, or for replication and dissemination (11). Severity of illness for SARS-CoV-2 infections is likely impacted by both the direct cytotoxic effects of the virus, and the effectiveness of the complex host response (12,13). While the immune response is essential to resolving the infection, dysregulation of the immune system can result in immunopathogenesis (14,15). A dysregulated immune response is caused by rapid viral replication, cytokine storms delayed interferon response, and macrophage infiltration and excessive proinflammatory cytokines (14). This immunopathogenesis mechanism is supported by the observation of decreased viral loads occurring with increased disease severity (6). However, efforts to unders...

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Section: Human Coronavirus (Hcov) Phylogenymentioning

confidence: 78%

Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection

Singh

Chen

Judy

et al. 2020

Preprint

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“…The co-expression of ACE2 and TMPRSS2 was reported in type 1 pneumocytes [195], alveolar macrophages [9,192], lymphocytes [9], smooth muscle cells and enterocytes in the gastrointestinal tract [9,195], vessel smooth muscle cells [9], cardiomyocytes [9,192], hepatocytes [169], kidney cells [87], proximal tubule cells [114], and neurons [112], all of which are in line with the common clinical symptoms of COVID-19 [15,19,61,151,166,183,191,197]. Single-cell RNA profiling revealed that male gender, advanced age, and smoking habit can increase the co-expression of ACE2 and TMPRESS2 Viral components are recognized by the MyD88 pathway in the endosome, leading to the releases of IL-6 and NFκB from immune cells including macrophages, monocytes, and dendrites.…”

Section: The Mechanisms Underlying Sars-cov-2 Infectionmentioning

confidence: 98%

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

et al. 2020

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The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional “receptor” and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the “cytokine storm.” Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

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“…We also analyzed the overlap of the ACE2+ signatures with SARS-CoV-2-implicated genes and ACE2 signature genes from multiple publicly available, independent studies and found significant shared components across SARS-CoV-2 datasets (Table 2). Specifically, genes associated with ACE2+ expression in DKD were also significantly enriched among host proteins identified to interact with SARS-CoV-2 proteins 33 , host genes upregulated in SARS-CoV-2infected cells 30,32 , and host proteins previously reported to interact with multiple coronaviruses 17 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

Section: Dkd (Supplementarymentioning

confidence: 99%

“…Studies of severe acute respiratory syndrome (SARS) in the early 2000s identified angiotensin-converting enzyme 2 (ACE2) as the primary cell-entry receptor for the SARS coronavirus (SARS-CoV) in humans 14,15 . Recent studies from the pandemic demonstrate that ACE2 is also the primary cell-entry receptor for SARS-CoV-2 13,16,17 and, similar to SARS-CoV, higher ACE2 expression may lead to higher risk of SARS-CoV-2 infection 8,18 .…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 receptor networks in diabetic and COVID-19 associated kidney disease

Menon

Sealfon

Nair

et al. 2020

Preprint

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COVID-19 morbidity and mortality is significantly increased in patients with diabetes and kidney disease via unknown mechanisms. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into human host cells, and ACE2 levels in target cells may influence SARS-CoV-2 susceptibility. We investigated how pre-existing conditions and drug treatments alter receptor expression in kidney tissue. Using single cell RNA profiling (scRNAseq) to assess ACE2 and associated SARS-CoV-2 proteases in healthy living donors (LD) kidneys, diabetic kidney disease (DKD), and in kidney injury during viral infection, ACE2 expression was primarily associated with proximal tubular epithelial cells (PTEC). ACE2 mRNA expression levels were significantly upregulated in DKD versus LD, however, ACE2 levels were not altered by exposures to renin angiotensin aldosterone system (RAAS) inhibitors. ACE2+ expression signatures were defined by differential expression analysis and characterized by Bayesian integrative analysis of a large compendium of public -omics datasets, resulting in the identification of network modules induced in ACE2 positive PTEC in DKD and BK virus nephropathy. These ACE2 upregulated cell programs were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing and overlapped significantly with the cellular responses induced by SARS-CoV-2 infection. Similar cellular programs were activated in ACE2-positive PTEC isolated in a urine sample from a COVID19 patient with acute kidney injury, suggesting a consistent ACE2-coregulated expression program that may interact with SARS-Cov-2 infection processes. The SARS-CoV-2 receptor associated gene signatures could seed further research into therapeutic strategies for COVID-19. Functional networks of gene expression signatures are available for further exploration to researchers at HumanBase

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Systemic analysis of tissue cells potentially vulnerable to SARS-CoV-2 infection by the protein-proofed single-cell RNA profiling of ACE2, TMPRSS2 and Furin proteases

Cited by 30 publications

References 53 publications

Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection

Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

SARS-CoV-2 receptor networks in diabetic and COVID-19 associated kidney disease

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