Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart

Liu, Hanning; Gai, Shujie; Wang, Xiaoyi; Zeng, Juntong; Sun, Cheng; Zhao, Yan; Zheng, Zhe

doi:10.1093/cvr/cvaa191

“… 55 Single-cell sequencing of ACE2 in the adult human heart demonstrated that male hearts have less ACE2 expressing cells compared to females. 56 Contrastingly, integration of single-cell atlas data has shown an association between male sex and increased expression of TMPRSS2, the main protease involved in SARS-CoV-2 cellular entry, as well as ACE2. 41 , 57 In addition, transcription of TMPRSS2 is regulated by an androgen receptor binding element in its promotor and androgenic ligands.…”

Section: Ace2 and Cellular Entry Of Sars-cov-2: Is There A Role For Smentioning

confidence: 98%

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Bienvenu

¹

,

Noonan

²

,

Wang

³

et al. 2020

Cardiovascular Research

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The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is a critical concern of the Coronavirus Disease 2019 (COVID-19) pandemic. Strikingly, men account for the majority of COVID-19 deaths, with current figures ranging from 59–75% of total mortality. However, despite clear implications in relation to COVID-19 mortality, most research has not considered sex as a critical factor in data analysis. Here, we highlight fundamental biological differences that exist between males and females, and how these may make significant contributions to the male-biased COVID-19 mortality. We present preclinical evidence identifying the influence of biological sex on the expression and regulation of angiotensin-converting enzyme 2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However, we note that there is a lack of reports showing that sexual dimorphism of ACE2 expression exists and is of functional relevance in humans. In contrast, there is strong evidence, especially in the context of viral infections, that sexual dimorphism plays a central role in the genetic and hormonal regulation of immune responses, both of the innate as well as the adaptive immune system. We review evidence supporting that ineffective anti-SARS-CoV-2 responses, coupled with a predisposition for inappropriate hyperinflammatory responses, could provide a biological explanation for the male bias in COVID-19 mortality. A prominent finding in COVID-19 is the increased risk of death with pre-existing cardiovascular comorbidities such as hypertension, obesity and age. We contextualise how important features of sexual dimorphism and inflammation in COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain their increased mortality risk. Ultimately, we demonstrate that biological sex is a fundamental variable of critical relevance to our mechanistic understanding of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and therapeutic strategies.

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“…Interestingly, not only ACE2 seems to be induced by interferon, but also its positive correlators, as well as those of ABL2 (which could be induced by the ISG ZNF267 according to our results), and the cathepsin L protease, CTSL . All of these are genes involved in the viral entry, and the latter activates the membrane fusion function of the spike viral protein S of SARS-CoV [ 60 ], and could substitute to the TMPRSS2 protease in cell types different to lung cells [ 61 ]. CTSL co-expressed genes are not only interferon but also interleukin induced genes, and three cytokines are co-expressed with it ( IL1B , CXCL2 and CXCL3 ).…”

Section: Discussionmentioning

confidence: 99%

Serial co-expression analysis of host factors from SARS-CoV viruses highly converges with former high-throughput screenings and proposes key regulators

Pérez-Pulido

¹

,

Asencio-Cortés

²

,

Brokate-Llanos

³

et al. 2021

Briefings in Bioinformatics

3

0

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The current genomics era is bringing an unprecedented growth in the amount of gene expression data, only comparable to the exponential growth of sequences in databases during the last decades. This data allow the design of secondary analyses that take advantage of this information to create new knowledge. One of these feasible analyses is the evaluation of the expression level for a gene through a series of different conditions or cell types. Based on this idea, we have developed Automatic and Serial Analysis of CO-expression, which performs expression profiles for a given gene along hundreds of heterogeneous and normalized transcriptomics experiments and discover other genes that show either a similar or an inverse behavior. It might help to discover co-regulated genes, and common transcriptional regulators in any biological model. The present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is an opportunity to test this novel approach due to the wealth of data that are being generated, which could be used for validating results. Thus, we have identified 35 host factors in the literature putatively involved in the infectious cycle of SARS-CoV viruses and searched for genes tightly co-expressed with them. We have found 1899 co-expressed genes whose assigned functions are strongly related to viral cycles. Moreover, this set of genes heavily overlaps with those identified by former laboratory high-throughput screenings (with P-value near 0). Our results reveal a series of common regulators, involved in immune and inflammatory responses that might be key virus targets to induce the coordinated expression of SARS-CoV-2 host factors.

show abstract

“…Interestingly, not only ACE2 seems to be induced by interferon, but also its positive correlators, as well as those of ABL2 (which could be induced by the ISG ZNF267 according to our results), and the cathepsin L protease, CTSL . All of these are genes involved in the viral entry, and the latter activates the membrane fusion function of the spike viral protein S of SARS-CoV (Bosch et al, 2008), and could substitute to the TMPRSS2 protease in cell types different to lung cells (Liu et al, 2020). CTSL co-expressed genes are not only interferon but also interleukin induced genes, and three cytokines are co-expressed with it ( IL1B, CXCL2 , and CXCL3 ).…”

Section: Discussionmentioning

confidence: 99%

Serial co-expression analysis of host factors from SARS-CoV viruses highly converges with former high-throughput screenings and proposes key regulators and co-option of cellular pathways

Pérez-Pulido

¹

,

Asencio-Cortés

²

,

Brokate-Llanos

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

The current genomics era is bringing an unprecedented growth in the amount of gene expression data, only comparable to the exponential growth of sequences in databases during the last decades. This data now allows the design of secondary analyses that take advantage of this information to create new knowledge through specific computational approaches. One of these feasible analyses is the evaluation of the expression level for a gene through a series of different conditions or cell types. Based on this idea, we have developed ASACO, Automatic and Serial Analysis of CO-expression, which performs expression profiles for a given gene along hundreds of normalized and heterogeneous transcriptomics experiments and discover other genes that show either a similar or an inverse behavior. It might help to discover co-regulated genes, and even common transcriptional regulators in any biological model, including human diseases or microbial infections. The present SARS-CoV-2 pandemic is an opportunity to test this novel approach due to the wealth of data that is being generated, which could be used for validating results. In addition, new cell mechanisms identified could become new therapeutic targets. Thus, we have identified 35 host factors in the literature putatively involved in the infectious cycle of SARS-CoV and/or SARS-CoV-2 and searched for genes tightly co-expressed with them. We have found around 1900 co-expressed genes whose assigned functions are strongly related to viral cycles. Moreover, this set of genes heavily overlap with those identified by former laboratory high-throughput screenings (with p-value near 0). Some of these genes aim to cellular structures such as the stress granules, which could be essential for the virus replication and thereby could constitute potential targets in the current fight against the virus. Additionally, our results reveal a series of common transcription regulators, involved in immune and inflammatory responses, that might be key virus targets to induce the coordinated expression of SARS-CoV-2 host factors. All of this proves that ASACO can discover gene co-regulation networks with potential for proposing new genes, pathways and regulators participating in particular biological systems.HighlightsASACO identifies regulatory associations of genes using public transcriptomics data.ASACO highlights new cell functions likely involved in the infection of coronavirus.Comparison with high-throughput screenings validates candidates proposed by ASACO.Genes co-expressed with host’s genes used by SARS-CoV-2 are related to stress granules.ZNF91 and TRIM14 might be putative targets to interfere with the viral infection.

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Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart

Cited by 78 publications

References 41 publications

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities

Serial co-expression analysis of host factors from SARS-CoV viruses highly converges with former high-throughput screenings and proposes key regulators

Serial co-expression analysis of host factors from SARS-CoV viruses highly converges with former high-throughput screenings and proposes key regulators and co-option of cellular pathways

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