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42-739: Bat coronavirus RaTG13 is a SARS-like betacoronavirus identified in the droppings of the horseshoe bat Rhinolophus affinis . It was discovered in 2013 in bat droppings from a mining cave near the town of Tongguan in Mojiang county in Yunnan , China . In February 2020, it was identified as the closest known relative of SARS-CoV-2 , the virus that causes COVID-19 , sharing 96.1% nucleotide identity . However, in 2022, scientists found three closer matches in bats found 530 km south, in Feuang , Laos, designated as BANAL-52 (96.8% identity), BANAL-103 and BANAL-236 . In
84-404: A factor of 1,000–5,000. The equivalent mouse rsACE2 did not have such an effect. This study suggests that rhsACE2 not only restores the renin-angiotensin system to balance as in the earlier ARDS studies, but also directly slows down infection by this virus – possibly as a decoy. ACE2 mutants have been engineered with even higher affinity for SARS-CoV-2 Spike and shown to effectively neutralise
126-543: A novel sequence of ribonucleic acids later identified as "RaTG13". In 2020, Shi and her group retested the serum samples from the miners for SARS-CoV-2. The samples tested negative. In 2020, the strain identified in the sample was renamed from the original Ra4991 (4991st sample collected from Rhinolophus affinis ) to "RaTG13", to reflect the originating bat species (Ra from Rhinolophus affinis ), geographic location (TG from Tongguan), and year collected (13 from 2013). The name change has been considered innuendo by advocates of
168-418: A possible cause of the infection, different animals (including bats, rats, and musk shrews ) were also sampled in and around the mining cave. Between 2012 and 2015, Shi Zhengli and her group isolated 293 different coronaviruses (284 alpha- and 9 beta-coronaviruses ) from bat feces samples in the cave. One of the samples collected in 2013 from Rhinolophus affinis (the intermediate horseshoe bat) contained
210-399: A stringent immunohistochemical analysis using two independent antibodies. In addition to the above-mentioned issues, mACE2 expression was also seen in endothelial cells and pericytes of blood vessels within certain tissues, cardiomyocytes in heart tissue, and a smaller subset of cells within the thyroid gland , epididymis , seminal vesicle , pancreas , liver and placenta . Despite
252-449: A study done during the SARS outbreak, SARS virus RNA was ascertained in the autopsy of heart specimens in 35% of the patients who died due to SARS. It was also observed that an already diseased heart has increased expression of mACE2 receptors contrasted to healthy individuals. This entry process also requires priming of the S protein by the host serine protease TMPRSS2 , the inhibition of which
294-475: Is a zinc-containing metalloenzyme located on the surface of intestinal enterocytes , renal tubular cells and other cells. mACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain. mACE2 is a single-pass type I membrane protein , with its enzymatically active domain exposed on the surface of cells in the intestines and other tissues. The extracellular domain of mACE2 can be cleaved from
336-558: Is about 10 hours, and the onset of action is 30 minutes in addition to the course of effect (duration) of 24 hours. Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classic renin–angiotensin system inhibitors (RAS inhibitors) or in diseases where circulating angiotensin II is elevated. An in vitro study focused on the early stages of infection found that clinical-grade human recombinant soluble ACE2 (hrsACE2) reduced SARS-CoV-2 recovery from vero cells by
378-465: Is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines , kidney , testis , gallbladder , and heart or in a soluble form (sACE2). Both membrane bound and soluble ACE2 are integral parts of the renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. mACE2 is cleaved by the enzyme ADAM17 in a process regulated by substrate presentation . ADAM17 cleavage releases
420-401: Is cleaved into 16 nonstructural proteins (see UniProt annotation of SARS rep , P0C6X7 ). As of May 2013, GenBank has 46 published complete genomes of the α- (group 1), β- (group 2), γ- (group 3), and δ- (group 4) CoVs. Genetic recombination can occur when two or more viral genomes are present in the same host cell. The dromedary camel Beta-CoV HKU23 exhibits genetic diversity in
462-466: Is created by the viral spike (S) peplomers , which are proteins that populate the surface of the virus and determine host tropism . The order Nidovirales is named for the Latin nidus , which means 'nest'. It refers to this order's production of a 3′-coterminal nested set of subgenomic mRNAs during infection. Several structures of the spike proteins have been resolved. The receptor binding domain in
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#1733094509225504-534: Is created during the Protective Phase of RAAS) is not only involved in binding to angiotensin II to create angiotensin I-7, which lowers blood pressure by vasodilation, but that free and soluble ACE2 may also be binding to coronavirus spike proteins , hence making those coronavirus spikes unavailable for binding to mACE-2 sites. But even with only tiny amounts of mACE2, SARS-CoV-2 virus can gain entry into cells if TMPRSS2
546-563: Is essential as it’s a cell surface receptor that lets the virus get into and infect cells. The spike protein’s RBD of SARS-CoV-2 links to ACE2, enabling viral entry and reproduction within cells. In addition the attachment of SP-A and SP-D residues to ACE2 could potentially diminish the strength of the interaction between the spike protein and ACE2. The binding of the SARS-CoV-2 virus through mACE2 receptors present in heart tissue may be responsible for direct viral injury leading to myocarditis. In
588-456: Is one of four genera ( Alpha -, Beta- , Gamma- , and Delta- ) of coronaviruses . Member viruses are enveloped , positive-strand RNA viruses that infect mammals , including humans . The natural reservoir for betacoronaviruses are bats and rodents. Rodents are the reservoir for the subgenus Embecovirus , while bats are the reservoir for the other subgenera. The coronavirus genera are each composed of varying viral lineages with
630-494: Is present. Both ACE inhibitors and angiotensin II receptor blockers (ARBs) that are used to treat high blood pressure have been shown in rodent studies to upregulate mACE2 expression, possibly affecting the severity of coronavirus infections. However, a systematic review and meta-analysis published on July 11, 2012, found that "use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls." Moreover, "the risk of pneumonia
672-451: Is the first betacoronavirus belonging to lineage C that is known to infect humans. The name "betacoronavirus" is derived from Ancient Greek βῆτα ( bē̂ta , "the second letter of the Greek alphabet "), and κορώνη (korṓnē, “garland, wreath”), meaning crown, which describes the appearance of the surface projections seen under electron microscopy that resemble a solar corona . This morphology
714-495: Is to act as a counterbalance to the angiotensin-converting enzyme (ACE). ACE cleaves angiotensin I hormone into the vasoconstricting angiotensin II which causes a cascade of hormonal reactions which is part of the body's harmful phase of RAAS, which ultimately leads to an increase in the body's blood pressure. ACE2 has an opposing effect to ACE, degrading angiotensin II into angiotensin (1-7) , thereby lowering blood pressure. sACE2, as part of RAAS's protective phase, cleaves
756-415: Is under current investigation as a potential therapeutic. It has also been shown that disruption of S-protein glycosylation significantly impairs viral entry, indicating the importance of glycan-protein interactions in the process. This has led some to hypothesize that decreasing the levels of mACE2, in cells, might help in fighting the infection. Furthermore, according to studies conducted on mice ,
798-527: The SARS-CoV-2 genome (it shares 96.1% nucleotide similarity), and its identification in animal droppings is a supporting piece of evidence for SARS-CoV-2's natural origin. The main area of divergence between RaTG13 and SARS-CoV-2 is in the receptor-binding domain (RBD) of the spike protein (S), which is the portion that binds to the receptor protein on the surface of the host cell and causes infection. The divergence in this domain indicates that, unlike SARS-CoV-2,
840-489: The lab leak theory for the COVID-19 pandemic . The sequence of RaTG13 was reconstructed from metagenomic sampling (a common practice in environmental virology), and as such, could potentially be an in-silico chimera . RaTG13 has not been confirmed to exist in nature, to have been cultured or isolated in any laboratory, or to be a viable human pathogen. A live virus "RaTG13" has never been detected in any laboratory sample from
882-637: The transmembrane domain by another enzyme known as ADAM17 a member of the sheddase enzyme family, during the protective phase of RAAS , the Renin–Angiotension–Aldosterone System, which regulates our body's blood pressure. The resulting cleaved protein is known as soluble ACE2 or sACE2. It is released into the bloodstream where one of sACE2's functions is to turn excess angiotensin II into angiotensin 1-7 which binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. Excess sACE2 may ultimately be excreted in
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#1733094509225924-700: The African camel population. Contributing to this diversity are several recombination events that had taken place in the past between closely related betacoronaviruses of the subgenus Embecovirus . Also the betacoronavirus, Human SARS-CoV , appears to have had a complex history of recombination between ancestral coronaviruses that were hosted in several different animal groups. Alpha- and betacoronaviruses mainly infect bats, but they also infect other species like humans , camels , and rodents . Betacoronaviruses that have caused epidemics in humans generally induce fever and respiratory symptoms. They include: Within
966-1704: The RaTG13 virus might not use angiotensin-converting enzyme 2 (ACE2) as its entry site into the cell. Further, the S protein of RaTG13 virus lacks the furin cleavage motif RRAR↓S. The binding affinity between RATG13 and hACE2 is lower than that between SARS-CoV-2 RBD and hACE2. A phylogenetic tree based on whole-genome sequences of SARS-CoV-2 and related coronaviruses is: ( Bat ) Rc-o319 , 81% to SARS-CoV-2, Rhinolophus cornutus , Iwate , Japan Bat SL-ZXC21 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan , Zhejiang Bat SL-ZC45 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan, Zhejiang Pangolin SARSr-CoV-GX, 85.3% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Pangolin SARSr-CoV-GD, 90.1% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Bat RshSTT182, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng , Cambodia Bat RshSTT200, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng, Cambodia (Bat) RacCS203 , 91.5% to SARS-CoV-2, Rhinolophus acuminatus , Chachoengsao , Thailand (Bat) RmYN02 , 93.3% to SARS-CoV-2, Rhinolophus malayanus , Mengla , Yunnan (Bat) RpYN06 , 94.4% to SARS-CoV-2, Rhinolophus pusillus , Xishuangbanna , Yunnan (Bat) RaTG13 , 96.1% to SARS-CoV-2, Rhinolophus affinis , Mojiang , Yunnan (Bat) BANAL-52 , 96.8% to SARS-CoV-2, Rhinolophus malayanus , Vientiane , Laos SARS-CoV-2 SARS-CoV-1 , 79% to SARS-CoV-2 Betacoronavirus Betacoronavirus (β-CoVs or Beta-CoVs)
1008-579: The SARS-CoV-2 entry receptor, it has been repeatedly hypothesised that population variation in ACE2 may contribute to an individual's genetic susceptibility to COVID-19. Several studies have reported that ACE2 missense variants can alter its binding affinity for the spike protein, and consequently its susceptibility to SARS-CoV-2 pseudovirus entry, and there is strong evidence of individuals who carry rare variants in ACE2 that could confer total resistance to SARS-CoV-2 infection. The expression level of ACE2 at
1050-478: The SARS-CoV-2 virus. Moreover, those variants have shown a 37% reduction in expression of the protein and a remarkable protection from severe outcomes (respiratory failure and death). Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy for acute lung injury , and appeared to improve pulmonary blood flow and oxygen saturation in piglets with a lipopolysaccharide -induced acute respiratory distress syndrome . The half-life of rhACE2 in human beings
1092-550: The WIV or elsewhere. Based on its sequence, RaTG13 is a positive-strand RNA virus with an outer membrane. Its genome is approximately 29,800 nucleotides. The genome encodes a replicase (ORF1a/1b) and four structural proteins; including a spike protein (S), membrane protein (M), envelope protein (E) and nucleocapsid protein (N); and five viral accessory proteins , including ORF3a (NS3), ORF6 (NS6), ORF7a (NS7a), ORF7b (NS7b) and ORF8 (NS8). RaTG13 bears strong resemblance to
1134-526: The alpha- and betacoronavirus spike protein is cataloged as InterPro : IPR018548 . The spike protein, a type 1 fusion machine , assembles into a trimer ( PDB : 3jcl , 6acg ); its core structure resembles that of paramyxovirus F (fusion) proteins. The receptor usage is not very conserved; for example, among Sarbecovirus , only a sub-lineage containing SARS share the ACE2 receptor. The viruses of subgenera Embecovirus differ from all others in
1176-564: The betacoronavirus genus containing four such lineages: A, B, C, D. In older literature, this genus is also known as "group 2 coronaviruses". The genus is in the subfamily Orthocoronavirinae in the family Coronaviridae , of the order Nidovirales . The betacoronaviruses of the greatest clinical importance concerning humans are OC43 and HKU1 (which can cause the common cold ) of lineage A, SARS-CoV-1 and SARS-CoV-2 (the causes of SARS and COVID-19 respectively) of lineage B, and MERS-CoV (the cause of MERS ) of lineage C. MERS-CoV
1218-442: The binding of the spike S1 protein of SARS-CoV and SARS-CoV-2 to the enzymatic domain of mACE2 on the surface of cells results in endocytosis and translocation of both the virus and the enzyme into endosomes located within cells. In culture blocking endocytosis traps the virus on the surface. The receptor-binding domain (RBD) of spike protein, located on the virus’s surface, specifically attaches to human cell receptors. ACE2
1260-438: The carboxyl-terminal amino acid phenylalanine from angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and hydrolyses it into the vasodilator angiotensin (1-7) (H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH), which binds to Mas Receptors and ultimately leads to a decrease in blood pressure. sACE2 can also cleave numerous peptides, including [des-Arg9]- bradykinin , apelin , neurotensin , dynorphin A , and ghrelin . mACE2 also regulates
1302-515: The cell surface is another critical factor affecting viral susceptibility and probably plays a role in the tissue tropism of the virus and many suspected COVID-19 associated ACE2 variants affect expression. In fact, SARS-CoV-2's viral tropism is dependent on ACE2 tissue distribution and expression. For example, genetic variants placed in the X chromosome (rs190509934:C) have been related to lower expression levels of ACE2 enzyme. This would lead to an increased number of entries and infections performed by
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1344-437: The entire process a promising drug target for treating cardiovascular diseases . mACE2 also serves as the entry point into cells for some coronaviruses , including HCoV-NL63 , SARS-CoV , and SARS-CoV-2 . The SARS-CoV-2 spike protein itself is known to damage the endothelium via downregulation of ACE2. The human version of the enzyme can be referred to as hACE2. Membrane bound angiotensin-converting enzyme 2 (mACE2)
1386-512: The extracellular domain creating soluble ACE2 (sACE2). ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing the hydrolysis of angiotensin II (a vasoconstrictor peptide which raises blood pressure) into angiotensin (1–7) (a vasodilator ). Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. This decrease in blood pressure makes
1428-421: The fact that the respiratory system is the primary route of SARS-CoV-2 infection, very limited expression is seen, both at protein and mRNA level. The expression within the respiratory system is mainly restricted to the upper bronchial and nasal epithelia , especially in the ciliated cells . As part of the renin–angiotensin–aldosterone system (RAAS) protective phase, soluble ACE2's (sACE2) important function
1470-1257: The genus Betacoronavirus (Group 2 CoV), four subgenera or lineages (A, B, C, and D) have traditionally been recognized. The four lineages have also been named using Greek letters or numerically. A fifth subgenus, Hibecovirus , was added more recently. Member subgenera and species include: Betacoronavirus 1 China Rattus coronavirus HKU24 Human coronavirus HKU1 Murine coronavirus Myodes coronavirus 2JL14 Severe acute respiratory syndrome–related coronavirus (SARSr-CoV or SARS-CoV) Hedgehog coronavirus 1 Middle East respiratory syndrome-related coronavirus (MERS-CoV) Pipistrellus bat coronavirus HKU5 Tylonycteris bat coronavirus HKU4 Eidolon bat coronavirus C704 Rousettus bat coronavirus GCCDC1 Rousettus bat coronavirus HKU9 Bat Hp-betacoronavirus Zhejiang2013 Angiotensin-converting enzyme 2 3SCL , 1R42 , 1R4L , 2AJF , 3D0G , 3D0H , 3D0I , 3KBH , 3SCI , 3SCJ , 3SCK 59272 70008 ENSG00000130234 ENSMUSG00000015405 Q9BYF1 Q8R0I0 NM_021804 NM_001371415 NM_001130513 NM_027286 NP_068576 NP_001358344 NP_001123985 NP_081562 Angiotensin-converting enzyme 2 ( ACE2 )
1512-447: The genus in that they have an additional shorter (8 nm) spike-like protein called hemagglutinin esterase (HE) ( P15776 ). It is believed to have been acquired from influenza C virus . Coronaviruses have a large genome size that ranges from 26 to 32 kilobases. The overall structure of β-CoV genome is similar to that of other CoVs, with an ORF1ab replicase polyprotein ( rep , pp1ab ) preceding other elements. This polyprotein
1554-451: The interaction of the spike protein of the coronavirus with mACE2 induces a drop in the levels of mACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage. On the other hand, sACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7 . Furthermore, some researchers have hypothesized that sACE2 (which
1596-633: The membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup's disease . Research in mice has shown that ACE2 (whether it is the membrane bound version or soluble is inconclusive) is involved in regulation of the blood glucose level but its mechanism is yet to be confirmed. As a transmembrane protein, mACE2 serves as the main entry point into cells for some coronaviruses , including HCoV-NL63 , SARS-CoV (the virus that causes SARS ), and SARS-CoV-2 (the virus that causes COVID-19 ). More specifically,
1638-599: The spring of 2012, three miners cleaning bat feces in an abandoned copper mine near the town of Tongguan in Mojiang Hani Autonomous County developed fatal pneumonia . Out of concerns that the miner's cases could represent a novel disease, serum samples collected from the miners were sent to the Wuhan Institute of Virology and tested by Shi Zhengli and her group for Ebola virus , Nipah virus , and bat SARSr-CoV Rp3. The samples tested negative. To uncover
1680-560: The urine. mACE2 is attached to the cell membrane of mainly enterocytes of the small intestine and duodenum , proximal tubular cells of the kidneys , glandular cells of the gallbladder , as well as Sertoli cells and Leydig cells of the testis . The expression profile of mACE2 in the human body was recently thoroughly evaluated by the Human Protein Atlas team using a large-scale multiomics approach combining several different methods for analysis of gene expression, including
1722-603: Was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure. Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia." An April 2020 study of patients hospitalized in Hubei Province in China found a death rate of 3.7% for patients with hypertension who were taking ACE inhibitors or ARBs. The death rate
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1764-784: Was compared with 9.8% of hospitalized patients with hypertension not taking such drugs, suggesting that ACE inhibitors and ARBs are not harmful and may help against the coronavirus. Despite lack of conclusive evidence, some have advocated for or against the cessation of ACE inhibitor or ARB treatment in COVID-19 patients with hypertension. However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy. Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients, with higher plasma levels being correlated with worse disease outcomes. Patients with high blood pressure or heart disease show elevated ACE2 plasma levels. Given its role as
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