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Key Event Title
SARS-CoV-2 cell entry
|Level of Biological Organization|
Key Event Components
|membrane fusion||transmembrane protease serine 2||occurrence|
|endocytosis involved in viral entry into host cell||cathepsin L1 (human)||occurrence|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|SARS-CoV-2 leads to acute respiratory distress||KeyEvent||Young Jun Kim (send email)||Open for comment. Do not cite||Under Development|
|SARS-CoV2 to thrombosis and DIC||KeyEvent||Shihori Tanabe (send email)||Under development: Not open for comment. Do not cite||Under Development|
|SARS-CoV-2 causes anosmia||KeyEvent||Sandra Coecke (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Sars-CoV-2 causes stroke||KeyEvent||Magda Sachana (send email)||Under development: Not open for comment. Do not cite||Under Development|
|SARS-CoV2 to hyperinflammation||KeyEvent||Hasmik Yepiskoposyan (send email)||Under development: Not open for comment. Do not cite|
|SARS-CoV2 to pyroptosis||KeyEvent||Hasmik Yepiskoposyan (send email)||Under development: Not open for comment. Do not cite|
|Pericytes possess a key role in the heart injury by COVID-19.||KeyEvent||Evangelos-Panagiotis Daskalopoulos (send email)||Under development: Not open for comment. Do not cite|
|SARS-CoV-2 leads to intestinal barrier disruption||KeyEvent||Laure-Alix Clerbaux (send email)||Under development: Not open for comment. Do not cite||Under Development|
|SARS-CoV-2 leads to infection proliferation||KeyEvent||Sally Mayasich (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Cytopathic SARS-CoV-2 leads to hyperinflammation||KeyEvent||Laure-Alix Clerbaux (send email)||Under development: Not open for comment. Do not cite|
|Homo sapiens||Homo sapiens||High||NCBI|
|Manis javanica||Manis javanica||Low||NCBI|
|Canis familiaris||Canis lupus familiaris||Moderate||NCBI|
|Macaca fascicularis||Macaca fascicularis||Not Specified||NCBI|
|Mesocricetus auratus||Mesocricetus auratus||Not Specified||NCBI|
|Mustela putorius furo||Mustela putorius furo||Not Specified||NCBI|
|Felis catus||Felis catus||Moderate||NCBI|
|Mustela lutreola||Mustela lutreola||High||NCBI|
|Neovison vison||Neovison vison||High||NCBI|
|Panthera tigris||Panthera tigris||Moderate||NCBI|
|All life stages||High|
Key Event Description
Coronavirus is recognized by the binding of S protein on the viral surface and angiotensin-converting enzyme 2 (ACE2) receptor on the cellular membrane, followed by viral entry via processing of S protein by transmembrane serine protease 2 (TMPRSS2) (Hoffmann et al., 2020b). ACE2 is expressed on epithelial cells of the lung and intestine, and also can be found in the heart, kidney, adipose, and male and female reproductive tissues (Lukassen et al., 2020, Lamers et al., 2020, Chen et al., 2020, Jing et al., 2020, Subramanian et al., 2020).
SARS-CoV-2 is an enveloped virus characterized by displaying spike proteins at the viral surface (Juraszek et al., 2021). Spike is critical for viral entry (Hoffmann et al., 2020b) and is the primary target of vaccines and therapeutic strategies, as this protein is the immunodominant target for antibodies (Yuan et al., 2020, Ju et al., 2020, Robbiani et al., 2020, Premkumar et al., 2020, Liu et al., 2020). Spike is composed of S1 and S2 subdomains. S1 contains the N-terminal (NTD) and receptor-binding (RBD) domains, and the S2 contains the fusion peptide (FP), heptad repeat 1 (HR1) and HR2, the transmembrane (TM) and cytoplasmic domains (CD) (Lan et al., 2020). S1 leads to the recognition of the angiotensin-converting enzyme 2 (ACE2) receptor and S2 is involved in membrane fusion (Hoffmann et al., 2020b, Letko et al., 2020, Shang et al., 2020).
Upon binding to ACE2, the spike protein needs to be activated (or primed) through proteolytic cleavage (by a host protease) to allow membrane fusion. Fusion is a key step in viral entry as it is the way to release SARS-CoV-2 genetic material inside the cell. Cleavage happens between its spike’s S1 and S2 domains, liberating S2 that inserts its N-terminal domain into a host cell membrane and mediates membrane fusion (Millet and Whittaker, 2018). Many proteases were identified to activate coronaviruses including furin, cathepsin L, trypsin-like serine proteases TMPRSS2, TMPRSS4, TMPRSS11, and human airway trypsin-like protease (HATs). These may operate at four different stages of the virus infection cycle: (a) pro-protein convertases (e.g., furin) during virus packaging in virus-producing cells, (b) extracellular proteases (e.g., elastase) after virus release into extracellular space, (c) cell surface proteases [e.g., type II transmembrane serine protease (TMPRSS2)] after virus attachment to virus-targeting cells, and (d ) lysosomal proteases (e.g., cathepsin L) after virus endocytosis in virus-targeting cells (Li, 2016). SARS-CoV-2 lipidic envelope may fuse with two distinct membrane types, depending on the host protease(s) responsible for cleaving the spike protein: (i) cell surface following activation by serine proteases such as TMPRSS2 and furin (Hoffmann et al., 2020b); or (ii) endocytic pathway within the endosomal–lysosomal compartments including processing by lysosomal cathepsin L (Yang and Shen, 2020). These flexibility for host cell factors mediating viral entry, highlights that the availability of factors existing in a cell type dictates the mechanism of viral entry (Kawase et al., 2012). When TMPRSS2 (or other serine proteases such as TMPRSS4 (Zang et al., 2020) or human airway trypsin-like protease [HAT] (Bestle et al., 2020a)) is expressed, fusion of the virus with the cell surface membrane is preferred (Shirato et al., 2018), while in their absence, the virus can penetrate the cell by endocytosis (Kawase et al., 2012). A third factor has also been shown to facilitate SARS-CoV-2 entry in cells that have ACE2 and even promote, although to very low levels, SARS-CoV-2 entry in cells that lack ACE2 and TMPRSS2 which is the neuropilin-1 (NRP-1) (Cantuti-Castelvetri et al., 2020). This key event deals with SARS-CoV-2 entry in host cells and is divided in three categories: TMPRSS2, capthesin L and NRP-1.
TMPRSS2 Spike cleavage:
TMPRSS2 (transmembrane serine protease 2, (https://www.ncbi.nlm.nih.gov/gene/7113) is a cell-surface protease (Hartenian et al., 2020) that facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. Viruses found to use this protein for cell entry include Influenza virus and the human coronaviruses HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2 (COVID-19 virus).
TMPRSS2 is a membrane bound serine protease also known as epitheliasin. TMPRSS2 belongs to the S1A class of serine proteases alongside proteins such as factor Xa and trypsin. Whilst there is evidence that TMPRSS2 autoclaves to generate a secreted protease, its physiological function has not been clearly identified. However, it is known to play a crucial role in facilitating entry of coronavirus particles into cells by cleaving the spike protein (Huggins, 2020).
After ACE2 receptor binding, SARS-CoV-2 S proteins can be subsequently cleaved and activated by host cell-surface protease at the S1/S2 and S2’ sites, generating the subunits S1 and S2 that remain non-covalently linked. Cleavage leads to activation of the S2 domain that drives fusion of the viral and host membranes (Hartenian et al., 2020, Walls et al., 2016). For other coronaviruses, processing of spike was proposed to be sequential with S1/S2 cleavage preceding that of S2. Cleavage at S1/S2 may be crucial for inducing conformational changes required for receptor binding or exposure of the S2 site to host proteases.
The S1/S2 site of SARS-CoV-2 S protein contains an insertion of four amino acids providing a minimal furin cleavage site (RRAR685↓) (that is absent in SARS-CoV). Interestingly, the furin cleavage site has been implicated in increased viral pathogensis (Bestle et al., 2020b, Huggins, 2020). Processing of the spike protein by furin at the S1/S2 cleavage site is thought to occur following viral replication in the endoplasmic reticulum Golgi intermediate compartment (ERGIC) (Hasan et al., 2020). The spike S2’ cleavage site of SARS-CoV-2 possesses a paired dibasic motif with a single KR segment (KR815↓) (as SARS-CoV) that is recognized by trypsin-like serine proteases such as TMPRSS2. The current data support a model for SARS-CoV-2 entry in which furin-mediated cleavage at the S1/S2 site pre-primes spike during biogenesis, facilitating the activation for membrane fusion by a second cleavage event at S2’ by TMPRSS2 following ACE2 binding (Bestle et al., 2020b, Johnson et al., 2020).
Camostat mesylate, an inhibitor of TMPRSS2, blocks SARS-CoV-2 infection of lung cells like Calu-3 cells but not Huh7.5 and Vero E6 cells. Cell entry was assessed using a viral isolate and viral pseudotypes (artificial viruses) expressing the COVID-19 spike (S) protein. The ability of the viral pseudotypes (expressing S protein from SARS-CoV and SARS-CoV-2) to enter human and animal cell lines was demonstrated, showing that SARS-CoV-2 can enter similar cell lines as SARS-CoV. Amino acid analysis and cell culture experiments showed that, like SARS-CoV, SARS-CoV-2 spike protein binds to human and bat angiotensin-converting enzyme 2 (ACE2) and uses a cellular protease TMPRSS2 for priming. Priming activates the spike protein to facilitate viral fusion and entry into cells. Cell culture experiments were performed using immortalized cell lines and primary human lung cells (Hoffmann et al., 2020b, Rahman et al., 2020).
Spike binding to neuropilin-1:
Neuropilin-1 (NRP1) is a transmembrane glycoprotein that serves as a cell surface receptor for semaphorins and various ligands involved in angiogenesis in vertebrates. NRP1 is expressed in neurons, blood vessels (endothelial cells), immune cells and many other cell types in the mammalian body (maternal fetal interface) and binds a range of structurally and functionally diverse extracellular ligands to modulate organ development and function (Raimondi et al., 2016). NRP1 is well described as a co-receptor for members of the class 3 semaphorins (SEMA3) or vascular endothelial growth factors (VEGFs) (Gelfand et al., 2014). Structurally, NRP1 comprises seven sub-domains, of which the first five are extracellular; two CUB domains (a1 and a2), two coagulation factor V/VIII domains (FV/VIII; b1 and b2) and a meprin, A5 μ-phosphatase domain (MAM; c). NRP1 contains only a short cytosolic tail with a PDZ-binding domain lacking internal signaling activity. The different ligand families bind to different sites of NRP1; SEMA3A binding requires the first three sub-domains of NRP1 (a1, a2, and b1), whereas binding of VEGF-A requires the b1 and b2 domains (Muhl et al., 2017). Additional studies conducted by means of in silico computational technology to identify and validate inhibitors of the interaction between NRP1 and SARS-CoV-2 Spike protein are reported in (Perez-Miller et al., 2020). Represents a schematic picture of VEGF-A triggered phosphorylation of VEGF-R2. Screening of NRP-1/VEGF-A165 inhibitors by in-cell Western (Perez-Miller et al., 2020).v NRP1 acts as a co-receptor for SARS-CoV-2.
NRP1 is a receptor for furin-cleaved SARS-CoV-2 spike peptide (Cantuti-Castelvetri et al., 2020, Daly et al., 2020, Johnson et al., 2020). Blockade of NRP1 reduces infectivity and entry, and alteration of the furin site leads to loss of NRP1 dependence, reduced replication in Calu3, augmented replication in Vero E6, and attenuated disease in a hamster pathogenesis disease model (Johnson et al., 2020). In fact, a small sequence of amino acids was found that appeared to mimic a protein sequence found in human proteins that interact with NRP1. The spike protein of SARS-CoV-2 binding with NRP1 aids viral infection of human cells. This was confirmed by applying a range of structural and biochemical approaches to establish that the spike protein of SARS-CoV-2 does indeed bind to NRP1. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic RRAR C-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors. It was reported that the S1 CendR motif directly bound NRP1 by X-ray crystallography and biochemical approaches. Blocking this interaction using RNAi or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture (Daly et al., 2020).
NRP1, known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was revealed by a monoclonal blocking antibody against NRP1. It was found that a SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells faced the nasal cavity (Cantuti-Castelvetri et al., 2020). Furthermore, it has been found that NRP1 is a new potential SARS‑CoV‑2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID‑19. Preclinical studies have suggested that NRP1, a transmembrane receptor that lacks a cytosolic protein kinase domain and exhibits high expression in the respiratory and olfactory epithelium, may also be implicated in COVID‑19 by enhancing the entry of SARS‑CoV‑2 into the brain through the olfactory epithelium. NRP1 is also expressed in the CNS, including olfactory‑related regions such as the olfactory tubercles and paraolfactory gyri. Supporting the potential role of NRP1 as an additional SARS‑CoV‑2 infection mediator implicated in the neurologic manifestations of COVID‑19. Accordingly, the neurotropism of SARS‑CoV‑2 via NRP1‑expressing cells in the CNS merits further investigation (Davies et al., 2020).
Up-regulation of NRP1 protein in diabetic kidney cells hints at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction (Mayi et al., 2021).
The main feature of NRP1 co-receptor is to form complexes with multiple other receptors. Hence, there is a competition between receptors to complex with NRP-1, which may determine their abilities both quantitatively and qualitatively to transduce signals. It is tempting to hypothesize that the occupancy of NRP-1 with one receptor may thus decrease its availability for virus entry. Recent proteomics work has shown that NRP-1 can form a complex with the α7 nicotinic receptor in mice. Both receptors are expressed in the human nasal and pulmonary epithelium (Mayi et al., 2021).
NRP1, is highly expressed in the respiratory and olfactory epithelium; it is also expressed in the CNS, including olfactory related regions such as the olfactory tubercles and paraolfactory gyri (Davies et al., 2020).
More information on tissue distribution and protein expression of NRP1 can be found in https://www.proteinatlas.org/ENSG000000992 50-NRP1
Spike entry via lysosomal cathepsins and endocytosis:
Evidence shows the role of TMPRSS2 and other serine proteases in activating the coronavirus spike protein for plasma membrane fusion. However, studies using various cell culture systems showed that SARS-CoV2 could enter cells via an alternative endosomal–lysosomal pathway. Evidence came from studies demonstrating that lysosomotropic agents reduced SARS-CoV replication in cells lacking TMPRSS2 and other studies, using highly potent and specific small-molecule cathepsin inhibitors, to understand the role of cathepsins in processing and activating the spike for membrane fusion, mainly of cathepsin L (one of the 11 cathepsins) (Rossi et al., 2004, Simmons et al., 2005). SARS-CoV-2 and other coronaviruses can establish infection through endosomal entry in commonly used in vitro cell culture systems. Of relevance, inhibitors of the endosomal pathway, as the cathepsin inhibitor Z-FA-FMK and PIKfyve inhibitor apilimod, blocked viral entry in Huh7.5 and Vero E6 cells but not Calu-3 cells.
Viral entry leads to delivery of virion proteins and translation of viral proteins immediately:
Coronavirus is a class of viruses that have single-stranded positive-sense RNA genomes in their envelopes [Kim D, et al., 2020]. The virus contains a 29.7 kB positive-sense RNA genome flanked by 5' and 3' untranslated regions of 265 and 342 nucleotides, respectively that contain cis-acting secondary RNA structures essential for RNA synthesis [Huston N. C. et al., 2021]. The genome just prior to the 5′ end contains the transcriptional regulatory sequence leader (TRS-L) [Budzilowicx C.J., et al., 1985]. The SARS-CoV genome is polycistronic and contains 14 open reading frames (ORFs) that are expressed by poorly understood mechanisms [Snijder E. J., et al., 2003]. Preceding each ORF there are other TRSs called the body TRS (TRS B). The 5′ two-thirds of the genome contains two large, overlapping, nonstructural ORFs and the 3′ third contains the remainder ORFs [Di H., et al., 2018]. Genome expression starts with the translation of two large ORFs of the 5’ two-thirds: ORF1a of 4382 amino acids and ORF1ab of 7073 amino acid that occurs via a programmed (- 1) ribosomal frameshifting [Snijder E. J., et al., 2003], yielding pp1a and pp1ab. These two polyproteins are cleaved into 16 subunits by two viral proteinases encoded by ORF1a, nsp3, and nsp5 that contain a papain-like protease domain and a 3C-like protease domain [Sacco M. D. et al., 2020]. The processing products are a group of replicative enzymes, named nsp1-nsp16, that assemble into a viral replication and transcription complex (RTC) associated with membranes of endoplasmic reticulum (ER) with the help of various membrane-associated viral proteins [Klein S., et al., 2021, Snijder E. J., et al., 2020, V'Kovski P. , et al., 2021]. This association leads to replication factories or organelles, that are originate new membranous structures that are observed by electron mciroscopy . They are a feature of all coronaviridae and the site of viral replication and transcription hidden from innate immune molecules.
How It Is Measured or Detected
SARS-CoV2 entry can be determined by many different ways:
1) quantitative RT-PCR specific to the subgenomic mRNA of the N transcript, in cells manipulated with host factors that express of not TMPRSS2, cathepsinL, neuropilin-1, hACE2 [Glowacka I, et al. (2011)], or exogenous addition of HAT or furin.
2) using spike-pseudotyped viral particles expressing GFP/luciferase/bgalactosidase and comparing with vesicular stomatitis virus G seudotyped particles expressing the same reporter analysed in manipulated cultured with cell lines, followed by determining fluorescence, biolumincescence, luciferase activity in cell lysates [Hoffmann M, et al. (2020)].
TMPRSS2 gene expression can be measured by RNAseq and microarray (Baughn et al., 2020).
Expression levels of TMPRSS2 can be measured by RNA in situ hybridization (RNA-ISH) (Qiao et al., 2020)
Several methods have been identified in the literature for measuring and detecting NRP1 receptor binding. Briefly described:
- X-ray crystallography and biochemical approaches help to show that the S1 CendR motif directly bound NRP1 (1). Binding of the S1 fragment to NRP1 was assessed and ability of SARS-CoV-2 to use NRP1 to infect cells was measured in angiotensin-converting enzyme-2 (ACE-2)-expressing cell lines by knocking out NRP1 expression, blocking NRP1 with 3 different anti-NRP1 monoclonal antibodies, or using NRP1 small molecule antagonists (Centers for Disease Control and Prevention, 2020, Daly et al., 2020).
Key findings (Centers for Disease Control and Prevention, 2020, Daly et al., 2020):
• The S1 fragment of the cleaved SARS-CoV-2 spike protein binds to the cell surface receptor neuropilin-1 (NRP1).
• SARS-CoV-2 utilizes NRP1 for cell entry as evidenced by decreased infectivity of cells in the presence of: NRP1 deletion (p <0.01). Three different anti-NRP1 monoclonal antibodies (p <0.001). Selective NRP1 antagonist, EG00229 (p <0.01).
- Cell lines were modified to express ACE2 and TMPRSS2, the two known SARS-CoV-2 host factors, and NRP1 to assess the contribution of NRP1 to infection. Autopsy specimens from multiple airway sites were stained with antibodies against SARS-CoV-2 proteins, ACE2, and NRP1, to visualize co-localization of proteins (6, 15).
Key findings (Cantuti-Castelvetri et al., 2020, Centers for Disease Control and Prevention, 2020):
• Infectivity of cells expressing angiotensin converting enzyme-2 (ACE2, receptor for SARS-CoV-2), transmembrane protease serine-2 (TSS2, primes the Spike [S] protein), and neuropilin-1 (NRP1) with pseudovirus expressing the SARS-CoV-2 S1 protein was approximately 3-fold higher than in cells expressing either ACE2 or TSS2 alone (p<0.05).
• Analysis of autopsy tissue from COVID-19 patients showed co-localization of the SARS-CoV-2 spike (S) protein and NRP1 in olfactory and respiratory epithelium.
Virtual screen of nearly 0.5 million compounds against the NRP-1 CendR site, resulting in nearly 1,000 hits. A pharmacophore model was derived from the identified ligands, considering both steric and electronic requirements. Preparation of receptor protein and grid for virtual screening, docking of known NRP-1 targeting compounds, ELISA based NRP1-VEGF-A165 protein binding assay; more details on methodology in the referenced paper (Perez-Miller et al., 2020)
Domain of Applicability
TMPRSS2 vertebrates (Lam et al., 2020)
NRP1 in human & rodents (but also present in monkey and other vertebrates (Lu and Meng, 2015)
The ability for SARS-CoV-2 to use multiple host pathways for viral entry, means that it is critical to map which viral entry pathway is prevalent in specific cell types. This is key for understanding coronavirus biology, but also use informed decisions to select cells for cell-based genetic and small-molecule screens and to interpret data. In fact, a combination of protease inhibitors that block both TRMPSS2 and cathepsin L is the most efficient combination to block coronavirus infection (Yamamoto et al., 2020, Shang et al., 2020, Shirato et al., 2018). In accordance, SARS-CoV-2 entry processes are highly dependent on endocytosis and endocytic maturation in cells that do not express TMPRSS2, such as VeroE6 or 293T cells (Murgolo et al., 2021, Kang et al., 2020, Mirabelli et al., 2020, Riva et al., 2020). However, even in these cells, heterologous expression of TMPRSS2 abrogates the pharmacological blockade of cathepsin inhibitors (Kawase et al., 2012, Hoffmann et al., 2020a). Treatment of SARS-CoV-2 with trypsin enables viral cell surface entry, even when TMPRSS2 is absent. Moreover, TMPRSS2 is more efficient to promote viral entry than cathepsins (Lamers et al., 2020), as when both factors are present,d cathepsin inhibitors are less effective than TMPRSS2 inhibitors (Hoffmann et al., 2020b). Therefore it is critical to map which cells contain the different types of proteases.
In summary, TMPRSS2 appears to be expressed in a wide range of healthy adult organs, but in restricted cell types, including:
- AT2 and clara cells of lungs
- sinusoidal endothelium, and hepatocyte of the liver,
- endocrine cells of the prostate,
- goblet cells , and enterocytes of the small intestine,
- intercalated cells, and the proximal tubular of the kidney.
- Ciliated, secretory and suprabasal of nasal
- spermatogonial stem cells of testes
- cyto tropoblast and peri vascular cells of placenta
- The nasal epithelium expresses various combinations of factors that, in principle, could facilitate SARS-CoV-2 infection, but it also expresses robust basal levels of RFs, which may act as a strong protective barrier in this tissue.
There is a shift in TMPRSS2 regulation during nasal epithelium differentiation in young individuals that is not occurring in old individuals (Lin et al., 1999, Lucas et al., 2008, Singh et al., 2020).
Only a small minority of human respiratory and intestinal cells have genes that express both ACE2 and TMPRSS2. Amongst the ones that do, three main cell types were identified: A) lung cells called type II pneumocytes (which help maintain air sacs, known as alveoli); B) intestinal cells called enterocytes, which help the body absorb nutrients; and C) goblet cells in the nasal passage, which secrete mucus (Ziegler et al., 2020).
The clinical manifestations of COVID‐19 include not only complications from acute myocardial injury, elevated liver enzymes, and acute kidney injury in patients presenting to hospitals, but also gastrointestinal symptoms in community patients experiencing milder forms of the disease (Madjid et al., 2020, Pan et al., 2020).
All life stages
The expression of isoforms 1 (NRP1) and 2 (NRP2) does not seem to overlap. Isoform 1 is expressed by the blood vessels of different tissues. In the developing embryo it is found predominantly in the nervous system. In adult tissues, it is highly expressed in heart and placenta; moderately in lung, liver, skeletal muscle, kidney and pancreas; and low in adult brain. Isoform 2 is found in liver hepatocytes, kidney distal and proximal tubules. Expressed in colon and 234 other tissues with Low tissue specificity (UniProtKB).
The expression of NRP1 protein in gastric cancer was not related to gender or age (Cao et al., 2020).
Androgen receptors (ARs) play a key role in the transcription of TMPRSS2 (Fig. 1). This may explain the predominance of males to COVID-19 infection, fatality, and severity because males tend to have a higher expression and activation of ARs than females, which is due to the presence of dihydrotestosterone (DHT).
Regulation of COVID-19 severity and fatality by sex hormones. Females have aromatase, the enzyme that converts androgen substrates into estrogen. On the other hand, males have steroid 5α reductase, the enzyme that is responsible for the conversion of testosterone into dihydrotestosterone (DHT). In case of males, DHT activates androgen receptor (AR) that binds to the androgen response element (ARE) present in the promoter of TMPRSS2 gene, leading to its transcription. This ultimately results into enhanced processing of viral spike protein for greater entry and spread of SARS-CoV-2 into host cells. On the other hand,in females, estrogen activates estrogen receptor (ER), which binds to the estrogen response element (ERE) present in the promoter of eNOS gene to drive its transcription and catalyze the formation of nitric oxide (NO) from L-arginine. This NO is involved in vasodilation as well as inhibition of viral replication.
For more information difference of NRP1 expression between male and female see https://www.proteinatlas.org/ENSG00000099250-NRP1/tissue.
The expression of NRP1 protein in gastric cancer was not related to gender, age. The expression of NRP1 protein in gastric cancer is closely correlated to clinical stage, tumor size, TNM stage, differentiation, and lymph node metastasis (Cao et al., 2020).
SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signalling to induce analgesia had same results on both male and female rodents (Moutal et al., 2020).
BAUGHN, L. B., SHARMA, N., ELHAIK, E., SEKULIC, A., BRYCE, A. H. & FONSECA, R. 2020. Targeting TMPRSS2 in SARS-CoV-2 Infection. Mayo Clin Proc, 95, 1989-1999.
BESTLE, D., HEINDL, M. R., LIMBURG, H., VAN LAM VAN, T., PILGRAM, O., MOULTON, H., STEIN, D. A., HARDES, K., EICKMANN, M., DOLNIK, O., ROHDE, C., KLENK, H.-D., GARTEN, W., STEINMETZER, T. & BÖTTCHER-FRIEBERTSHÄUSER, E. 2020a. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Science Alliance, 3.
BESTLE, D., HEINDL, M. R., LIMBURG, H., VAN LAM VAN, T., PILGRAM, O., MOULTON, H., STEIN, D. A., HARDES, K., EICKMANN, M., DOLNIK, O., ROHDE, C., KLENK, H. D., GARTEN, W., STEINMETZER, T. & BOTTCHER-FRIEBERTSHAUSER, E. 2020b. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci Alliance, 3.
BUDZILOWICZ, C.J., WILCZYNSKI, S.P., AND WEISS, S.R. (1985). Three intergenic regions of coronavirus mouse hepatitis virus strain A59 genome RNA contain a common nucleotide sequence that is homologous to the 3' end of the viral mRNA leader sequence. J Virol 53, 834-840.
CANTUTI-CASTELVETRI, L., OJHA, R., PEDRO, L. D., DJANNATIAN, M., FRANZ, J., KUIVANEN, S., VAN DER MEER, F., KALLIO, K., KAYA, T., ANASTASINA, M., SMURA, T., LEVANOV, L., SZIROVICZA, L., TOBI, A., KALLIO-KOKKO, H., OSTERLUND, P., JOENSUU, M., MEUNIER, F. A., BUTCHER, S. J., WINKLER, M. S., MOLLENHAUER, B., HELENIUS, A., GOKCE, O., TEESALU, T., HEPOJOKI, J., VAPALAHTI, O., STADELMANN, C., BALISTRERI, G. & SIMONS, M. 2020. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science, 370, 856-860.
CAO, H., LI, Y., HUANG, L., BAI, B. & XU, Z. 2020. Clinicopathological Significance of Neuropilin 1 Expression in Gastric Cancer: A Meta-Analysis. Dis Markers, 2020, 4763492.
CENTERS FOR DISEASE CONTROL AND PREVENTION, U. S. D. O. H. A. H. S. 2020. Covid-19 Science Update 2020.
CHEN, L., LI, X., CHEN, M., FENG, Y. & XIONG, C. 2020. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res, 116, 1097-1100.
DALY, J. L., SIMONETTI, B., KLEIN, K., CHEN, K. E., WILLIAMSON, M. K., ANTON-PLAGARO, C., SHOEMARK, D. K., SIMON-GRACIA, L., BAUER, M., HOLLANDI, R., GREBER, U. F., HORVATH, P., SESSIONS, R. B., HELENIUS, A., HISCOX, J. A., TEESALU, T., MATTHEWS, D. A., DAVIDSON, A. D., COLLINS, B. M., CULLEN, P. J. & YAMAUCHI, Y. 2020. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science, 370, 861-865.
DAVIES, J., RANDEVA, H. S., CHATHA, K., HALL, M., SPANDIDOS, D. A., KARTERIS, E. & KYROU, I. 2020. Neuropilin1 as a new potential SARSCoV2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID19. Mol Med Rep, 22, 4221-4226.
DI, H., MCINTYRE, A.A., AND BRINTON, M.A. (2018). New insights about the regulation of Nidovirus subgenomic mRNA synthesis. Virology 517, 38-43.
GELFAND, M. V., HAGAN, N., TATA, A., OH, W. J., LACOSTE, B., KANG, K. T., KOPYCINSKA, J., BISCHOFF, J., WANG, J. H. & GU, C. 2014. Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding. Elife, 3, e03720.
HARTENIAN, E., NANDAKUMAR, D., LARI, A., LY, M., TUCKER, J. M. & GLAUNSINGER, B. A. 2020. The molecular virology of coronaviruses. J Biol Chem, 295, 12910-12934.
HASAN, A., PARAY, B. A., HUSSAIN, A., QADIR, F. A., ATTAR, F., AZIZ, F. M., SHARIFI, M., DERAKHSHANKHAH, H., RASTI, B., MEHRABI, M., SHAHPASAND, K., SABOURY, A. A. & FALAHATI, M. 2020. A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin. J Biomol Struct Dyn, 1-9.
HOFFMANN, M., KLEINE-WEBER, H. & POHLMANN, S. 2020a. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol Cell, 78, 779-784 e5.
HOFFMANN, M., KLEINE-WEBER, H., SCHROEDER, S., KRUGER, N., HERRLER, T., ERICHSEN, S., SCHIERGENS, T. S., HERRLER, G., WU, N. H., NITSCHE, A., MULLER, M. A., DROSTEN, C. & POHLMANN, S. 2020b. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181, 271-280 e8.
HUGGINS, D. J. 2020. Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2. J Mol Graph Model, 100, 107710.
HUSTON, N.C., WAN, H., STRINE, M.S., DE CESARIS ARAUJO TAVARES, R., WILEN, C.B., AND PYLE, A.M. (2021). Comprehensive in vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms. Mol Cell 81, 584-598 e585.
JING, Y., RUN-QIAN, L., HAO-RAN, W., HAO-RAN, C., YA-BIN, L., YANG, G. & FEI, C. 2020. Potential influence of COVID-19/ACE2 on the female reproductive system. Mol Hum Reprod, 26, 367-373.
JOHNSON, B. A., XIE, X., KALVERAM, B., LOKUGAMAGE, K. G., MURUATO, A., ZOU, J., ZHANG, X., JUELICH, T., SMITH, J. K., ZHANG, L., BOPP, N., SCHINDEWOLF, C., VU, M., VANDERHEIDEN, A., SWETNAM, D., PLANTE, J. A., AGUILAR, P., PLANTE, K. S., LEE, B., WEAVER, S. C., SUTHAR, M. S., ROUTH, A. L., REN, P., KU, Z., AN, Z., DEBBINK, K., SHI, P. Y., FREIBERG, A. N. & MENACHERY, V. D. 2020. Furin Cleavage Site Is Key to SARS-CoV-2 Pathogenesis. bioRxiv.
JU, B., ZHANG, Q., GE, J., WANG, R., SUN, J., GE, X., YU, J., SHAN, S., ZHOU, B., SONG, S., TANG, X., YU, J., LAN, J., YUAN, J., WANG, H., ZHAO, J., ZHANG, S., WANG, Y., SHI, X., LIU, L., ZHAO, J., WANG, X., ZHANG, Z. & ZHANG, L. 2020. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature, 584, 115-119.
JURASZEK, J., RUTTEN, L., BLOKLAND, S., BOUCHIER, P., VOORZAAT, R., RITSCHEL, T., BAKKERS, M. J. G., RENAULT, L. L. R. & LANGEDIJK, J. P. M. 2021. Stabilizing the closed SARS-CoV-2 spike trimer. Nat Commun, 12, 244.
KANG, Y.-L., CHOU, Y.-Y., ROTHLAUF, P. W., LIU, Z., SOH, T. K., CURETON, D., CASE, J. B., CHEN, R. E., DIAMOND, M. S., WHELAN, S. P. J. & KIRCHHAUSEN, T. 2020. Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2. bioRxiv, 2020.04.21.053058.
KAWASE, M., SHIRATO, K., VAN DER HOEK, L., TAGUCHI, F. & MATSUYAMA, S. 2012. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J Virol, 86, 6537-45.
KIM, D., LEE, J.Y., YANG, J.S., KIM, J.W., KIM, V.N., AND CHANG, H. (2020). The Architecture of SARS-CoV-2 Transcriptome. Cell 181, 914-921 e910.
KLEIN, S., CORTESE, M., WINTER, S.L., WACHSMUTH-MELM, M., NEUFELDT, C.J., CERIKAN, B., STANIFER, M.L., BOULANT, S., BARTENSCHLAGER, R., AND CHLANDA, P. (2020). SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography. Nat Commun 11, 5885.
LAM, S. D., BORDIN, N., WAMAN, V. P., SCHOLES, H. M., ASHFORD, P., SEN, N., VAN DORP, L., RAUER, C., DAWSON, N. L., PANG, C. S. M., ABBASIAN, M., SILLITOE, I., EDWARDS, S. J. L., FRATERNALI, F., LEES, J. G., SANTINI, J. M. & ORENGO, C. A. 2020. SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals. Sci Rep, 10, 16471.
LAMERS, M. M., BEUMER, J., VAN DER VAART, J., KNOOPS, K., PUSCHHOF, J., BREUGEM, T. I., RAVELLI, R. B. G., PAUL VAN SCHAYCK, J., MYKYTYN, A. Z., DUIMEL, H. Q., VAN DONSELAAR, E., RIESEBOSCH, S., KUIJPERS, H. J. H., SCHIPPER, D., VAN DE WETERING, W. J., DE GRAAF, M., KOOPMANS, M., CUPPEN, E., PETERS, P. J., HAAGMANS, B. L. & CLEVERS, H. 2020. SARS-CoV-2 productively infects human gut enterocytes. Science, 369, 50-54.
LAN, J., GE, J., YU, J., SHAN, S., ZHOU, H., FAN, S., ZHANG, Q., SHI, X., WANG, Q., ZHANG, L. & WANG, X. 2020. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 581, 215-220.
LETKO, M., MARZI, A. & MUNSTER, V. 2020. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol, 5, 562-569.
LI, F. 2016. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu Rev Virol, 3, 237-261.
LIN, B., FERGUSON, C., WHITE, J. T., WANG, S., VESSELLA, R., TRUE, L. D., HOOD, L. & NELSON, P. S. 1999. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res, 59, 4180-4.
LIU, L., WANG, P., NAIR, M. S., YU, J., RAPP, M., WANG, Q., LUO, Y., CHAN, J. F., SAHI, V., FIGUEROA, A., GUO, X. V., CERUTTI, G., BIMELA, J., GORMAN, J., ZHOU, T., CHEN, Z., YUEN, K. Y., KWONG, P. D., SODROSKI, J. G., YIN, M. T., SHENG, Z., HUANG, Y., SHAPIRO, L. & HO, D. D. 2020. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature, 584, 450-456.
LU, Y. & MENG, Y. G. 2015. Quantitation of Circulating Neuropilin-1 in Human, Monkey, Mouse, and Rat Sera by ELISA. Methods Mol Biol, 1332, 39-48.
LUCAS, J. M., TRUE, L., HAWLEY, S., MATSUMURA, M., MORRISSEY, C., VESSELLA, R. & NELSON, P. S. 2008. The androgen-regulated type II serine protease TMPRSS2 is differentially expressed and mislocalized in prostate adenocarcinoma. J Pathol, 215, 118-25.
LUKASSEN, S., CHUA, R. L., TREFZER, T., KAHN, N. C., SCHNEIDER, M. A., MULEY, T., WINTER, H., MEISTER, M., VEITH, C., BOOTS, A. W., HENNIG, B. P., KREUTER, M., CONRAD, C. & EILS, R. 2020. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J, 39, e105114.
MADJID, M., SAFAVI-NAEINI, P., SOLOMON, S. D. & VARDENY, O. 2020. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol, 5, 831-840.
MAYI, B. S., LEIBOWITZ, J. A., WOODS, A. T., AMMON, K. A., LIU, A. E. & RAJA, A. 2021. The role of Neuropilin-1 in COVID-19. PLoS Pathog, 17, e1009153.
MILLET, J. K. & WHITTAKER, G. R. 2018. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology, 517, 3-8.
MIRABELLI, C., WOTRING, J. W., ZHANG, C. J., MCCARTY, S. M., FURSMIDT, R., FRUM, T., KADAMBI, N. S., AMIN, A. T., O’MEARA, T. R., PRETTO, C. D., SPENCE, J. R., HUANG, J., ALYSANDRATOS, K. D., KOTTON, D. N., HANDELMAN, S. K., WOBUS, C. E., WEATHERWAX, K. J., MASHOUR, G. A., O’MEARA, M. J. & SEXTON, J. Z. 2020. Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19. bioRxiv, 2020.05.27.117184.
MOUTAL, A., MARTIN, L. F., BOINON, L., GOMEZ, K., RAN, D., ZHOU, Y., STRATTON, H. J., CAI, S., LUO, S., GONZALEZ, K. B., PEREZ-MILLER, S., PATWARDHAN, A., IBRAHIM, M. M. & KHANNA, R. 2020. SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia. bioRxiv.
MUHL, L., FOLESTAD, E. B., GLADH, H., WANG, Y., MOESSINGER, C., JAKOBSSON, L. & ERIKSSON, U. 2017. Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D-PDGFRbeta signaling. J Cell Sci, 130, 1365-1378.
MUKHERJEE, S. & PAHAN, K. 2021. Is COVID-19 Gender-sensitive? J Neuroimmune Pharmacol, 16, 38-47.
MURGOLO, N., THERIEN, A. G., HOWELL, B., KLEIN, D., KOEPLINGER, K., LIEBERMAN, L. A., ADAM, G. C., FLYNN, J., MCKENNA, P., SWAMINATHAN, G., HAZUDA, D. J. & OLSEN, D. B. 2021. SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS Pathog, 17, e1009225.
PAN, X. W., XU, D., ZHANG, H., ZHOU, W., WANG, L. H. & CUI, X. G. 2020. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis. Intensive Care Med, 46, 1114-1116.
PEREZ-MILLER, S., PATEK, M., MOUTAL, A., CABEL, C. R., THORNE, C. A., CAMPOS, S. K. & KHANNA, R. 2020. In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein. bioRxiv.
PREMKUMAR, L., SEGOVIA-CHUMBEZ, B., JADI, R., MARTINEZ, D. R., RAUT, R., MARKMANN, A., CORNABY, C., BARTELT, L., WEISS, S., PARK, Y., EDWARDS, C. E., WEIMER, E., SCHERER, E. M., ROUPHAEL, N., EDUPUGANTI, S., WEISKOPF, D., TSE, L. V., HOU, Y. J., MARGOLIS, D., SETTE, A., COLLINS, M. H., SCHMITZ, J., BARIC, R. S. & DE SILVA, A. M. 2020. The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci Immunol, 5.
QIAO, Y., WANG, X. M., MANNAN, R., PITCHIAYA, S., ZHANG, Y., WOTRING, J. W., XIAO, L., ROBINSON, D. R., WU, Y. M., TIEN, J. C., CAO, X., SIMKO, S. A., APEL, I. J., BAWA, P., KREGEL, S., NARAYANAN, S. P., RASKIND, G., ELLISON, S. J., PAROLIA, A., ZELENKA-WANG, S., MCMURRY, L., SU, F., WANG, R., CHENG, Y., DELEKTA, A. D., MEI, Z., PRETTO, C. D., WANG, S., MEHRA, R., SEXTON, J. Z. & CHINNAIYAN, A. M. 2020. Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2. Proc Natl Acad Sci U S A.
RAHMAN, N., BASHARAT, Z., YOUSUF, M., CASTALDO, G., RASTRELLI, L. & KHAN, H. 2020. Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2). Molecules, 25.
RAIMONDI, C., BRASH, J. T., FANTIN, A. & RUHRBERG, C. 2016. NRP1 function and targeting in neurovascular development and eye disease. Prog Retin Eye Res, 52, 64-83.
RIVA, L., YUAN, S., YIN, X., MARTIN-SANCHO, L., MATSUNAGA, N., BURGSTALLER-MUEHLBACHER, S., PACHE, L., DE JESUS, P. P., HULL, M. V., CHANG, M., CHAN, J. F.-W., CAO, J., POON, V. K.-M., HERBERT, K., NGUYEN, T.-T., PU, Y., NGUYEN, C., RUBANOV, A., MARTINEZ-SOBRIDO, L., LIU, W.-C., MIORIN, L., WHITE, K. M., JOHNSON, J. R., BENNER, C., SUN, R., SCHULTZ, P. G., SU, A., GARCIA-SASTRE, A., CHATTERJEE, A. K., YUEN, K.-Y. & CHANDA, S. K. 2020. A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals. bioRxiv, 2020.04.16.044016.
ROBBIANI, D. F., GAEBLER, C., MUECKSCH, F., LORENZI, J. C. C., WANG, Z., CHO, A., AGUDELO, M., BARNES, C. O., GAZUMYAN, A., FINKIN, S., HAGGLOF, T., OLIVEIRA, T. Y., VIANT, C., HURLEY, A., HOFFMANN, H. H., MILLARD, K. G., KOST, R. G., CIPOLLA, M., GORDON, K., BIANCHINI, F., CHEN, S. T., RAMOS, V., PATEL, R., DIZON, J., SHIMELIOVICH, I., MENDOZA, P., HARTWEGER, H., NOGUEIRA, L., PACK, M., HOROWITZ, J., SCHMIDT, F., WEISBLUM, Y., MICHAILIDIS, E., ASHBROOK, A. W., WALTARI, E., PAK, J. E., HUEY-TUBMAN, K. E., KORANDA, N., HOFFMAN, P. R., WEST, A. P., JR., RICE, C. M., HATZIIOANNOU, T., BJORKMAN, P. J., BIENIASZ, P. D., CASKEY, M. & NUSSENZWEIG, M. C. 2020. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature, 584, 437-442.
ROSSI, A., DEVERAUX, Q., TURK, B. & SALI, A. 2004. Comprehensive search for cysteine cathepsins in the human genome. Biol Chem, 385, 363-72.
SACCO, M.D., MA, C., LAGARIAS, P., GAO, A., TOWNSEND, J.A., MENG, X., DUBE, P., ZHANG, X., HU, Y., KITAMURA, N., et al. (2020). Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M(pro) and cathepsin L. Sci Adv 6(50):eabe0751.
SHANG, J., WAN, Y., LUO, C., YE, G., GENG, Q., AUERBACH, A. & LI, F. 2020. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A, 117, 11727-11734.
SHIRATO, K., KAWASE, M. & MATSUYAMA, S. 2018. Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry. Virology, 517, 9-15.
SIMMONS, G., GOSALIA, D. N., RENNEKAMP, A. J., REEVES, J. D., DIAMOND, S. L. & BATES, P. 2005. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A, 102, 11876-81.
SINGH, M., BANSAL, V. & FESCHOTTE, C. 2020. A single-cell RNA expression map of human coronavirus entry factors. bioRxiv.
SNIJDER, E.J., BREDENBEEK, P.J., DOBBE, J.C., THIEL, V., ZIEBUHR, J., POON, L.L.M., GUAN, Y., ROZANOV, M., SPAAN, W.J.M., AND GORBALENYA, A.E. (2003). Unique and Conserved Features of Genome and Proteome of SARS-coronavirus, an Early Split-off From the Coronavirus Group 2 Lineage. Journal of Molecular Biology 331, 991-1004.
SNIJDER, E.J., LIMPENS, R., DE WILDE, A.H., DE JONG, A.W.M., ZEVENHOVEN-DOBBE, J.C., MAIER, H.J., FAAS, F., KOSTER, A.J., AND BARCENA, M. (2020). A unifying structural and functional model of the coronavirus replication organelle: Tracking down RNA synthesis. PLoS Biol 18, e3000715.
SUBRAMANIAN, A., VERNON, K. A., SLYPER, M., WALDMAN, J., LUECKEN, M. D., GOSIK, K., DUBINSKY, D., CUOCO, M. S., KELLER, K., PURNELL, J., NGUYEN, L., DIONNE, D., ROZENBLATT-ROSEN, O., WEINS, A., REGEV, A. & GREKA, A. 2020. RAAS blockade, kidney disease, and expression of ACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells.
UNIPROTKB - O14786 (NRP1_HUMAN)
V'KOVSKI, P., KRATZEL, A., STEINER, S., STALDER, H., AND THIEL, V. (2021). Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. 19, 155–170.
WALLS, A. C., TORTORICI, M. A., BOSCH, B. J., FRENZ, B., ROTTIER, P. J. M., DIMAIO, F., REY, F. A. & VEESLER, D. 2016. Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer. Nature, 531, 114-117.
WANG, Y., LIU, M. & GAO, J. 2020. Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. Proc Natl Acad Sci U S A, 117, 13967-13974.
YAMAMOTO, M., KISO, M., SAKAI-TAGAWA, Y., IWATSUKI-HORIMOTO, K., IMAI, M., TAKEDA, M., KINOSHITA, N., OHMAGARI, N., GOHDA, J., SEMBA, K., MATSUDA, Z., KAWAGUCHI, Y., KAWAOKA, Y. & INOUE, J. I. 2020. The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner. Viruses, 12.
YANG, N. & SHEN, H.-M. 2020. Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19. International Journal of Biological Sciences, 16, 1724-1731.
YUAN, M., WU, N. C., ZHU, X., LEE, C. D., SO, R. T. Y., LV, H., MOK, C. K. P. & WILSON, I. A. 2020. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science, 368, 630-633.
ZANG, R., GOMEZ CASTRO, M. F., MCCUNE, B. T., ZENG, Q., ROTHLAUF, P. W., SONNEK, N. M., LIU, Z., BRULOIS, K. F., WANG, X., GREENBERG, H. B., DIAMOND, M. S., CIORBA, M. A., WHELAN, S. P. J. & DING, S. 2020. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol, 5.
ZIEGLER, C. G. K., ALLON, S. J., NYQUIST, S. K., MBANO, I. M., MIAO, V. N., TZOUANAS, C. N., CAO, Y., YOUSIF, A. S., BALS, J., HAUSER, B. M., FELDMAN, J., MUUS, C., WADSWORTH, M. H., 2ND, KAZER, S. W., HUGHES, T. K., DORAN, B., GATTER, G. J., VUKOVIC, M., TALIAFERRO, F., MEAD, B. E., GUO, Z., WANG, J. P., GRAS, D., PLAISANT, M., ANSARI, M., ANGELIDIS, I., ADLER, H., SUCRE, J. M. S., TAYLOR, C. J., LIN, B., WAGHRAY, A., MITSIALIS, V., DWYER, D. F., BUCHHEIT, K. M., BOYCE, J. A., BARRETT, N. A., LAIDLAW, T. M., CARROLL, S. L., COLONNA, L., TKACHEV, V., PETERSON, C. W., YU, A., ZHENG, H. B., GIDEON, H. P., WINCHELL, C. G., LIN, P. L., BINGLE, C. D., SNAPPER, S. B., KROPSKI, J. A., THEIS, F. J., SCHILLER, H. B., ZARAGOSI, L. E., BARBRY, P., LESLIE, A., KIEM, H. P., FLYNN, J. L., FORTUNE, S. M., BERGER, B., FINBERG, R. W., KEAN, L. S., GARBER, M., SCHMIDT, A. G., LINGWOOD, D., SHALEK, A. K., ORDOVAS-MONTANES, J., LUNG-NETWORK@HUMANCELLATLAS.ORG, H. C. A. L. B. N. E. A. & NETWORK, H. C. A. L. B. 2020. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell, 181, 1016-1035 e19.