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• W3017632090 abstract "In as few as 3 months, coronavirus disease 2019 (COVID-19) has spread and ravaged the world at an unprecedented speed in modern history, rivaling the 1918 flu pandemic. Severe acute respiratory syndrome coronavirus-2, the culprit virus, is highly contagious and stable in the environment and transmits predominantly among humans via the respiratory route. Accumulating evidence suggest that this virus, like many of its related viruses, may also be an enteric virus that can spread via the fecal–oral route. Such a hypothesis would also contribute to the rapidity and proliferation of this pandemic. Here we briefly summarize what is known about this family of viruses and literature basis of the hypothesis that severe acute respiratory syndrome coronavirus-2 is capable of infecting the gastrointestinal tract and shedding in the environment for potential human-to-human transmission. In as few as 3 months, coronavirus disease 2019 (COVID-19) has spread and ravaged the world at an unprecedented speed in modern history, rivaling the 1918 flu pandemic. Severe acute respiratory syndrome coronavirus-2, the culprit virus, is highly contagious and stable in the environment and transmits predominantly among humans via the respiratory route. Accumulating evidence suggest that this virus, like many of its related viruses, may also be an enteric virus that can spread via the fecal–oral route. Such a hypothesis would also contribute to the rapidity and proliferation of this pandemic. Here we briefly summarize what is known about this family of viruses and literature basis of the hypothesis that severe acute respiratory syndrome coronavirus-2 is capable of infecting the gastrointestinal tract and shedding in the environment for potential human-to-human transmission. Coronaviruses (CoVs) are ubiquitous in nature and infect a wide range of animals, causing diseases involving the respiratory, gastrointestinal (GI), and neurological systems.1Fung T.S. Liu D.X. Human coronavirus: host-pathogen interaction.Annu Rev Microbiol. 2019; 73: 529-557Crossref PubMed Scopus (621) Google Scholar Before 2000, only 2 species of CoVs (HCoV-229E and HCoV-OC43) were known to infect humans and cause mild respiratory illness.2Weiss S.R. Forty years with coronaviruses.J Exp Med. 2020; : 217Google Scholar Two other species of human CoVs (HCoV-NL63 and HCoV-HKU1) were isolated in the early 2000s. Since then, the human race has encountered the following 3 novel CoV outbreaks: severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, Middle East respiratory syndrome (MERS)-CoV in 2012, and the ongoing SARS-CoV-2, all of which have jumped species from animals to humans and are associated with severe respiratory disease and high mortality. Zoonotic infections involving nonhuman species as intermediate hosts, such as invertebrate vectors, rodents, and bats, are common in nature.3Plowright R.K. Parrish C.R. McCallum H. et al.Pathways to zoonotic spillover.Nat Rev Microbiol. 2017; 15: 502-510Crossref PubMed Scopus (496) Google Scholar But cross-species jumps from animals to humans with altered tropism as a result of genetic alterations are less frequent. At present, it is not clear what accounts for this seemingly increased pace of cross-species transmission of such virulent pathogens that can cause devastating disease in humans. Manipulation of the environment by mankind, increased human–animal contacts, and globalization may have facilitated conditions for cross-species infection.4Johnson C.K. Hitchens P.L. Pandit P.S. et al.Global shifts in mammalian population trends reveal key predictors of virus spillover risk.Proc Biol Sci. 2020; 287: 20192736Crossref PubMed Scopus (264) Google Scholar At the time this review was completed (April 23, 2020), coronavirus disease 2019 (COVID-19) has emerged as a world pandemic. Globally SARS-CoV-2 has infected 2,667,532 people, of which 850,116 cases are identified in the United States alone. Currently, no clinically approved specific antivirals (except the recently demonstrated benefit of remdesivir), other therapeutic remedies, or vaccines are available for this disease. Although spread of the virus among humans is predominantly through respiratory droplets, questions remain regarding other potential modes of transmission that may contribute to the initial cross-species infection, a large number asymptomatic cases, and the rapid and unusual pattern of dissemination across the globe. In this review, we provide a summary of the molecular biology of the virus, evidence for its infection of cells within the gastrointestinal and hepatotropic/biliary tracts, and implications for potential fecal–oral transmission of the virus. For more extensive review of the virus and its associated diseases, we refer to other review articles and brief summaries.5Gu J. Han B. Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission.Gastroenterology. 2020 May; 158: 1518-1519Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar, 6Hindson J. COVID-19: faecal-oral transmission?.Nat Rev Gastroenterol Hepatol. 2020; 17: 259Crossref PubMed Scopus (235) Google Scholar, 7Yeo C. Kaushal S. Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible?.Lancet Gastroenterol Hepatol. 2020; 5: 335-337Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar, 8Tian Y. Rong L. Nian W. et al.Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission.Aliment Pharmacol Ther. 2020; 51: 843-851Crossref PubMed Scopus (600) Google Scholar, 9Wong S.H. Lui R.N. Sung J.J. Covid-19 and the digestive system.J Gastroenterol Hepatol. 2020; 35: 744-748Crossref PubMed Scopus (468) Google Scholar CoVs belong to the Coronaviridae family within the Nidovirales order. They are enveloped, nonsegmented, positive-sense RNA viruses with a large genome of approximately 30 kb. Figure 1 illustrates the schematic replication cycle of the virus. The initial attachment of the CoV to the host cell is mediated by interactions between the spike glycoprotein (S) and its cognate receptor. This molecular interaction is a major determinant of species, tissue, and cell tropism of a CoV. Many CoVs utilize cell-surface peptidases as their receptors, but the peptidase activity seems to be dispensable for viral entry.10Li F. Receptor recognition mechanisms of coronaviruses: a decade of structural studies.J Virol. 2015; 89: 1954-1964Crossref PubMed Scopus (390) Google Scholar Many alphacoronaviruses use aminopeptidase N.11Delmas B. Gelfi J. L'Haridon R. et al.Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV.Nature. 1992; 357: 417-420Crossref PubMed Scopus (504) Google Scholar,12Yeager C.L. Ashmun R.A. Williams R.K. et al.Human aminopeptidase N is a receptor for human coronavirus 229E.Nature. 1992; 357: 420-422Crossref PubMed Scopus (685) Google Scholar In the case of SARS-CoV and SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2) mediates entry into host cells,13Li W. Moore M.J. Vasilieva N. et al.Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426: 450-454Crossref PubMed Scopus (4369) Google Scholar, 14Zhou P. Yang X.L. Wang X.G. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (13649) Google Scholar, 15Hoffmann M. Kleine-Weber H. Schroeder S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280.e8Abstract Full Text Full Text PDF PubMed Scopus (12600) Google Scholar whereas dipeptidyl-peptidase 4 (DPP4) is the receptor for MERS-CoV.16Raj V.S. Mou H. Smits S.L. et al.Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC.Nature. 2013; 495: 251-254Crossref PubMed Scopus (1514) Google Scholar Of note, ACE2 is an X-linked gene and has sex-specific expression profiles17Tukiainen T. Villani A.C. Yen A. et al.Landscape of X chromosome inactivation across human tissues.Nature. 2017; 550: 244-248Crossref PubMed Scopus (533) Google Scholar that may contribute to the observed more severe clinical manifestations in males compared to females with COVID-19.18Cai H. Sex difference and smoking predisposition in patients with COVID-19.Lancet Respir Med. 2020; 8e20Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar Smokers and individuals with chronic obstructive pulmonary disease have higher ACE2 expression levels.19Leung J.M. Yang C.X. Tam A. et al.ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19.Eur Respir J. 2020; 55Crossref Scopus (564) Google Scholar Innate immune signaling such as interferon also seems to regulate ACE2 levels and thus susceptibility to SARS-CoV-2 infection.20Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues [published online ahead of print April 27, 2020]. Cell https://doi.org/10.1016/j.cell.2020.04.035.Google Scholar In the context of the GI tract, patients with enteric virus infections and other inflammatory conditions may have a different cytokine profile and thus distinct ACE2 levels in the gut. In addition, genetic polymorphisms in the ACE2 gene have been associated with diabetes and hypertension.21Lu N. Yang Y. Wang Y. et al.ACE2 gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects.Mol Biol Rep. 2012; 39: 6581-6589Crossref PubMed Scopus (59) Google Scholar,22Wu Y.H. Li J.Y. Wang C. et al.The ACE2 G8790A polymorphism: involvement in type 2 diabetes mellitus combined with cerebral stroke.J Clin Lab Anal. 2017; 31Crossref Scopus (53) Google Scholar Whether they are linked to clinical outcomes in COVID-19 patients remains to be tested and may shed light on the role of genetic predisposition to more severe diseases. Interestingly, these viral receptors have been the targets of drug development for cardiac disease, hypertension, and diabetes, with ACE inhibitors blocking the renin-angiotensin-aldosterone system and gliptins inhibiting the DPP4 action to improve glucose control. While the enzymatic actions of these peptidases are dispensable for viral infection, these inhibitors can result in the up-regulation of the protein, offering an intriguing hypothesis that patients with hypertension and diabetes are often on these drugs and thus may be more susceptible to more severe COVID-19 disease.4Johnson C.K. Hitchens P.L. Pandit P.S. et al.Global shifts in mammalian population trends reveal key predictors of virus spillover risk.Proc Biol Sci. 2020; 287: 20192736Crossref PubMed Scopus (264) Google Scholar Multiple Cryo-EM structures of the recombinant S receptor binding domain and ACE2 complex have already been solved with an unprecedented speed.23Lan J. Ge J. Yu J. et al.Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581: 215-220Crossref PubMed Scopus (3674) Google Scholar, 24Shang J. Ye G. Shi K. et al.Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581: 221-224Crossref PubMed Scopus (2384) Google Scholar, 25Tai W, He L, Zhang X, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine [published online ahead of print March 19, 2020]. Cell Mol Immunol https://doi.org/10.1038/s41423-020-0400-4.Google Scholar, 26Yan R. Zhang Y. Li Y. et al.Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.Science. 2020; 367: 1444-1448Crossref PubMed Scopus (3321) Google Scholar These data indicate that the receptor-binding domain of S binds tightly to human and bat ACE2, suggestive of a zoonotic origin. A recent study demonstrated that the virus can indeed be transmitted to cats (including recent news of transmission to tigers in the Bronx Zoo) and ferrets, but not dogs, chickens, or pigs,24Shang J. Ye G. Shi K. et al.Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581: 221-224Crossref PubMed Scopus (2384) Google Scholar although porcine ACE2 mediates viral entry in cell culture.14Zhou P. Yang X.L. Wang X.G. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (13649) Google Scholar This broad species tropism raises concerns of potential transmission from domestic pets to humans and vice versa. From a structural and immunogen design perspective, more information is needed regarding the native S protein trimeric state on virions, how the trimer interacts with ACE2, and how such interaction is disrupted by neutralizing antibodies. A recent publication on the crystal structure of an antibody in complex with the receptor-binding domain of the SARS-CoV-2 S protein provides important molecular insight into antibody recognition of the virus and a potential strategy for vaccine development.27Yuan M. Wu N.C. Zhu X. et al.A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV.Science. 2020; 368: 630-633Crossref PubMed Scopus (947) Google Scholar Besides ACE2, other potential entry factors, such as CD14728Wang K, Chen W, Zhou Y-S, et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv Preprint https://doi.org/10.1101/2020.03.14.988345.Google Scholar and integrins,29Sigrist C.J. Bridge A. Le Mercier P. A potential role for integrins in host cell entry by SARS-CoV-2.Antiviral Res. 2020; 177: 104759Crossref PubMed Scopus (226) Google Scholar are currently under investigation. After receptor engagement, SARS-CoV-2 gains access into the host cell. Like other human CoVs, this process is generally accomplished by acid-dependent proteolytic cleavage of S protein proteases such as cathepsins, which exposes the fusion domain of the S protein in the endosome,30Park J.E. Li K. Barlan A. et al.Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism.Proc Natl Acad Sci U S A. 2016; 113: 12262-12267Crossref PubMed Scopus (206) Google Scholar or by transmembrane serine protease 2 (TMPRSS2) at the plasma membrane.31Glowacka I. Bertram S. Muller M.A. et al.Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response.J Virol. 2011; 85: 4122-4134Crossref PubMed Scopus (773) Google Scholar,32Shirato K. Kawase M. Matsuyama S. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2.J Virol. 2013; 87: 12552-12561Crossref PubMed Scopus (319) Google Scholar For MERS-CoV, furin-mediated cleavage and fusion also occurs during virus entry,33Millet J.K. Whittaker G.R. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein.Proc Natl Acad Sci U S A. 2014; 111: 15214-15219Crossref PubMed Scopus (475) Google Scholar and may be relevant for SARS-CoV-2.34Bestle DH, Heindl MR, Limburg MR, et al. TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-1 CoV-2 in human airway epithelial cells and provide promising drug targets. bioRxiv Preprint https://doi.org/10.1101/2020.04.15.042085.Google Scholar This step takes place before fusion of the viral and cellular membranes and is also a key determinant of tissue and species tropism of the virus.35Menachery V.D. Dinnon 3rd, K.H. Yount Jr., B.L. et al.Trypsin treatment unlocks barrier for zoonotic bat coronavirus infection.J Virol. 2020; 94Crossref PubMed Scopus (116) Google Scholar This acid-dependent process may explain the proposed efficacy of chloroquine or hydroxychloroquine, as a lysosomotropic agent, in the treatment of COVID-1936Cortegiani A, Ingoglia G, Ippolito M, et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 [published online ahead of print March 10, 2020]. J Crit Care https://doi.org/10.1016/j.jcrc.2020.03.005.Google Scholar (Figure 1). Recent publications suggest that, similar to SARS-CoV, trypsin and TMPRSS2 also prime SARS-CoV-2 S protein for efficient infection.15Hoffmann M. Kleine-Weber H. Schroeder S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280.e8Abstract Full Text Full Text PDF PubMed Scopus (12600) Google Scholar,37Ou X. Liu Y. Lei X. et al.Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.Nat Commun. 2020; 11: 1620Crossref PubMed Scopus (2119) Google Scholar Overexpression of TMPRSS2 in African green monkey Vero-E6 cells significantly enhanced SARS-CoV-2 infectivity.38Matsuyama S. Nao N. Shirato K. et al.Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells.Proc Natl Acad Sci U S A. 2020; 117: 7001-7003Crossref PubMed Scopus (863) Google Scholar Serine protease inhibitor camostat blocked SARS-CoV-2 entry into host cells in a dose-dependent manner,15Hoffmann M. Kleine-Weber H. Schroeder S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280.e8Abstract Full Text Full Text PDF PubMed Scopus (12600) Google Scholar making it and other similar inhibitors, such as nafamostat39Wang M. Cao R. Zhang L. et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.Cell Res. 2020; 30: 269-271Crossref PubMed Scopus (4784) Google Scholar and Pharos compounds (CHEMBL1229259), candidate small-molecule inhibitors in the treatment of COVID-19 patients (Figure 1). Besides the respiratory tract, including oral mucosa,40Xu H. Zhong L. Deng J. et al.High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa.Int J Oral Sci. 2020; 12: 8Crossref PubMed Scopus (1760) Google Scholar the GI tract, in particular the small intestine, has high expression levels of ACE2 and TMPRSS2 in both humans41Uhlen M. Fagerberg L. Hallstrom B.M. et al.Proteomics. Tissue-based map of the human proteome.Science. 2015; 347: 1260419Crossref PubMed Scopus (8255) Google Scholar and mice.42Wu C. Orozco C. Boyer J. et al.BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources.Genome Biol. 2009; 10: R130Crossref PubMed Scopus (1127) Google Scholar Multiple data sets of single-cell RNA-sequencing analysis indicated that mature absorptive enterocytes from ileum and colon have high ACE2 messenger RNA expression levels.43Martin J.C. Chang C. Boschetti G. et al.Single-cell analysis of Crohn's disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy.Cell. 2019; 178: 1493-1508 e20Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 44Smillie C.S. Biton M. Ordovas-Montanes J. et al.Intra- and inter-cellular rewiring of the human colon during ulcerative colitis.Cell. 2019; 178: 714-730 e22Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 45Wang Y. Song W. Wang J. et al.Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine.J Exp Med. 2020; 217Crossref Scopus (6) Google Scholar ACE2 protein levels have been validated by immunostaining in human small intestinal epithelium.46Hamming I. Timens W. Bulthuis M.L. et al.Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.J Pathol. 2004; 203: 631-637Crossref PubMed Scopus (4013) Google Scholar On the luminal surface of intestinal epithelial cells, ACE2 associates with the neutral amino acid transporter B0AT1 and regulates intestinal microflora.47Camargo S.M. Singer D. Makrides V. et al.Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations.Gastroenterology. 2009; 136: 872-882Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar,48Hashimoto T. Perlot T. Rehman A. et al.ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.Nature. 2012; 487: 477-481Crossref PubMed Scopus (913) Google Scholar SARS-CoV-2 infection of the GI tract, by altering the levels of ACE2 at the brush border, can cause microbial dysbiosis and inflammation. In addition, high ACE2 expression is also evident in cholangiocytes and, to a lesser extent, hepatocytes, and suggests possible hepatobiliary infection by SARS-CoV-2.49Chai XH, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv Preprint https://doi.org/10.1101/2020.02.03.931766.Google Scholar As major human pathogens of medical significance, CoVs cause a variety of diseases in animals.50Weiss S.R. Leibowitz J.L. Coronavirus pathogenesis.Adv Virus Res. 2011; 81: 85-164Crossref PubMed Scopus (570) Google Scholar For instance, the prototypic mouse hepatitis virus infects the lung and spreads systemically to the GI tract, liver, and brain, causing gastroenteritis, hepatitis, and encephalitis. Transmissible gastroenteritis virus and porcine epidemic diarrhea virus cause severe gastroenteritis in young piglets, leading to significant morbidity and mortality. Avian infectious bronchitis virus is a major cause of economic loss within the poultry industry. Bat CoV infects the GI and respiratory tracts of the bats without apparent diseases. Feline enteric CoV causes a mild or asymptomatic infection in domestic cats. It is clear from the names of these animal CoVs that they are entero-pathogens and the primary symptoms point to an intestinal tropism. Figure 2 illustrates the species and tissue tropisms of the common human and animal CoVs and diseases they are known to cause. The receptors of the human pathogens, HCoV-229E, SARS-CoV, and MERS-CoV, are aminopeptidase N (also known as CD13), ACE2, and DPP4 (also known as CD26), respectively, all brush-border enzymes highly expressed on the apical surface of mature enterocytes.51Bai J.P. Distribution of brush-border membrane peptidases along the intestine of rabbits and rats: implication for site-specific delivery of peptide drugs.J Drug Target. 1993; 1: 231-236Crossref PubMed Scopus (13) Google Scholar GI involvements were frequently reported in both SARS-CoV and MERS-CoV infections. During the SARS outbreak, up to 76% of patients with SARS developed diarrhea, usually within the first week of illness.52Kwan A.C. Chau T.N. Tong W.L. et al.Severe acute respiratory syndrome-related diarrhea.J Gastroenterol Hepatol. 2005; 20: 606-610Crossref PubMed Scopus (19) Google Scholar Intestinal biopsy demonstrated active SARS-CoV replication within both the small and large intestines and infectious virus was isolated from intestinal tissue but not fecal specimens.53Leung W.K. To K.F. Chan P.K. et al.Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection.Gastroenterology. 2003; 125: 1011-1017Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar In 2012, during the MERS outbreak, one-quarter of patients with MERS-CoV reported GI symptoms, including diarrhea and abdominal pain, before the manifestation of respiratory symptoms54Assiri A. Al-Tawfiq J.A. Al-Rabeeah A.A. et al.Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study.Lancet Infect Dis. 2013; 13: 752-761Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar and active shedding of viral RNA could be detected in the stool of these patients, although no infectious virus was recovered.55Corman V.M. Albarrak A.M. Omrani A.S. et al.Viral shedding and antibody response in 37 patients with Middle East Respiratory syndrome coronavirus infection.Clin Infect Dis. 2016; 62: 477-483PubMed Google Scholar MERS virus was shown to actively replicate in primary human intestinal enteroids and can be transmitted enterically to human DPP4 transgenic mice with replication in intestinal epithelium, enterocolitis, and subsequent spread to other organs.56Zhou J. Li C. Zhao G. et al.Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus.Sci Adv. 2017; 3eaao4966Crossref PubMed Scopus (272) Google Scholar Frequent liver involvement has also been reported in SARS and MERS infections, mostly with mild to moderate elevations of aminotransferases (more than 2 times the upper limit of normal).57Xu L. Liu J. Lu M. et al.Liver injury during highly pathogenic human coronavirus infections.Liver Int. 2020; 40: 998-1004Crossref PubMed Scopus (582) Google Scholar Viral RNA and particles have been detected in the liver of SARS patients on autopsy.58Zhang Q.L. Ding Y.Q. 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Known enteric CoVs, like transmissible gastroenteritis virus, can resist these harsh conditions by heavy glycosylation of S protein, evolving intrinsic resistance to low pH and digestive enzymes, and forming a tight complex with mucins.60Holmes K.V. Enteric infections with coronaviruses and toroviruses.Novartis Found Symp. 2001; 238 (discussion 269–275): 258-269Crossref PubMed Google Scholar Both SARS-CoV and MERS-CoV are intrinsically capable of enduring harsh conditions: SARS-CoV is viable for up to 2 weeks after drying and up to 5 days in room temperature and low humidity.61Chan K.H. Peiris J.S. Lam S.Y. et al.The effects of temperature and relative humidity on the viability of the SARS coronavirus.Adv Virol. 2011; 2011: 734690Crossref PubMed Scopus (619) Google Scholar MERS-CoV appears to be similarly hardy.62van Doremalen N. Bushmaker T. Munster V.J. 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• W3017632090 title "Is SARS-CoV-2 Also an Enteric Pathogen With Potential Fecal–Oral Transmission? A COVID-19 Virological and Clinical Review" @default.
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