Main Clinical Features of COVID-19 and Potential Prognostic and Therapeutic Value of the Microbiota in SARS-CoV-2 Infections

Yu He, Jianhui Wang, Fang Li, Yuan Shi, Yu He, Jianhui Wang, Fang Li, Yuan Shi

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has become a pandemic, infecting more than 4,000,000 people worldwide. This review describes the main clinical features of COVID-19 and potential role of microbiota in COVID-19. SARS-CoV and SARS-CoV-2 have 79.5% nucleotide sequence identity and use angiotensin-converting enzyme 2 (ACE2) receptors to enter host cells. The distribution of ACE2 may determine how SARS-CoV-2 infects the respiratory and digestive tract. SARS and COVID-19 share similar clinical features, although the estimated fatality rate of COVID-19 is much lower. The communication between the microbiota and SARS-CoV-2 and the role of this association in diagnosis and treatment are unclear. Changes in the lung microbiota were identified in COVID-19 patients, and the enrichment of the lung microbiota with bacteria found in the intestinal tract is correlated with the onset of acute respiratory distress syndrome and long-term outcomes. ACE2 regulates the gut microbiota by indirectly controlling the secretion of antimicrobial peptides. Moreover, the gut microbiota enhances antiviral immunity by increasing the number and function of immune cells, decreasing immunopathology, and stimulating interferon production. In turn, respiratory viruses are known to influence microbial composition in the lung and intestine. Therefore, the analysis of changes in the microbiota during SARS-CoV-2 infection may help predict patient outcomes and allow the development of microbiota-based therapies.

Keywords: ACE2; COVID-19; SARS-CoV-2; SCFAs; microbiota.

Copyright © 2020 He, Wang, Li and Shi.

Figures

Figure 1
Figure 1
ACE2 and the microbiota. The intestinal uptake of tryptophan is mediated by B0AT1, and ACE2 is indispensable for the expression of B0AT1. Tryptophan stimulates the secretion of antimicrobial peptides through the mTOR pathway. Changes in the levels of antimicrobial peptides can influence the composition of the gut microbiota. AMP, antimicrobial peptides; Trp, tryptophan.

References

    1. Abt M. C., Osborne L. C., Monticelli L. A., Doering T. A., Alenghat T., Sonnenberg G. F., et al. . (2012). Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37, 158–170. 10.1016/j.immuni.2012.04.011
    1. Antunes K. H., Fachi J. L., De Paula R., Da Silva E. F., Pral L. P., Dos Santos A., et al. . (2019). Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response. Nat Commun. 10:3273. 10.1038/s41467-019-11152-6
    1. Assiri A., Al-Tawfiq J. A., Al-Rabeeah A. A., Al-Rabiah F. A., Al-Hajjar S., Al-Barrak A., et al. . (2013). Epidemiological, demographic, and clinical characteristics of 47 cases of middle east respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect. Dis. 13, 752–761. 10.1016/S1473-3099(13)70204-4
    1. Atarashi K., Tanoue T., Oshima K., Suda W., Honda K. (2013). Treg induction by a rationally selected mixture of clostridia strains from the human microbiota. Nature 500, 232–236. 10.1038/nature12331
    1. Bartley J. M., Zhou X., Kuchel G. A., Weinstock G. M., Haynes L. (2017). Impact of age, caloric restriction, and influenza infection on mouse gut microbiome: an exploratory study of the role of age-related microbiome changes on influenza responses. Front. Immunol. 8:1164. 10.3389/fimmu.2017.01164
    1. Cao X. (2020). COVID-19: immunopathology and its implications for therapy. Nat. Rev. Immunol. 20, 269–270. 10.1038/s41577-020-0308-3
    1. Cebula A., Seweryn M., Rempala G. A., Pabla S. S., Mcindoe R. A., Denning T. L., et al. . (2013). Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497, 258–262. 10.1038/nature12079
    1. Chan J. F.-W., Yuan S., Kok K.-H., To K. K.-W., Chu H., Yang J., et al. . (2020). A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 395, 514–523. 10.1016/S0140-6736(20)30154-9
    1. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., et al. . (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, China: a descriptive study. Lancet. 395, 507–513. 10.1016/S0140-6736(20)30211-7
    1. Cheung K. S., Hung I. F., Chan P. P., Lung K. C., Tso E., Liu R., et al. . (2020). Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from the hong kong cohort and systematic review and meta-analysis. Gastroenterology. 10.1053/j.gastro.2020.03.065. [Epub ahead of print].
    1. del Rio C., Malani P. N. (2020). COVID-19-new insights on a rapidly changing epidemic. JAMA 323, 1339–1340. 10.1001/jama.2020.3072
    1. Deriu E., Boxx G. M., He X., Pan C., Benavidez S. D., Cen L., et al. . (2016). Influenza virus affects intestinal microbiota and secondary salmonella infection in the gut through type I interferons. PLoS Pathog. 12:e1005572. 10.1371/journal.ppat.1005572
    1. Diao B., Wang C., Tan Y., Chen X., Liu Y., Ning L., et al. . (2020). Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front. Immunol. 11:827. 10.3389/fimmu.2020.00827
    1. Dickson R. P., Schultz M. J., Van Der Poll T., Schouten L. R., Falkowski N. R., Luth J. E., et al. . (2020). Lung microbiota predict clinical outcomes in critically III patients. Am. J. Respir. Crit. Care Med. 01, 555–563. 10.1164/rccm.201907-1487OC
    1. Dickson R. P., Singer B. H., Newstead M. W., Falkowski N. R., Erb-Downward J. R., Standiford T. J., et al. . (2016). Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat. Microbiol. 1:16113. 10.1038/nmicrobiol.2016.113
    1. Donnelly C. A., Ghani A. C., Leung G. M., Hedley A. J., Fraser C., Riley S., et al. . (2003). Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong. Lancet 361, 1761–1766. 10.1016/S0140-6736(03)13410-1
    1. Drosten C., Gunther S., Preiser W., Van Der Werf S., Brodt H. R., Becker S., et al. . (2003). Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N. Engl. J. Med. 348, 1967–1976. 10.1056/NEJMoa030747
    1. Furusawa Y., Obata Y., Fukuda S., Endo T. A., Nakato G., Takahashi D., et al. . (2013). Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450. 10.1038/nature12721
    1. Gagneur A., Dirson E., Audebert S., Vallet S., Legrand-Quillien M. C., Laurent Y., et al. . (2008). Materno-fetal transmission of human coronaviruses: a prospective pilot study. Eur. J. Clin. Microbiol. Infect. Dis. 27, 863–866. 10.1007/s10096-008-0505-7
    1. Gomersall C. D., Joynt G. M. (2013). Middle east respiratory syndrome: new disease, old lessons. Lancet 381, 2229–2230. 10.1016/S0140-6736(13)61412-9
    1. Goyal P., Choi J. J., Pinheiro L. C., Schenck E. J., Chen R., Jabri A., et al. . (2020). Clinical characteristics of covid-19 in New York city. N. Engl. J. Med. 10.1056/NEJMc2010419. [Epub ahead of print].
    1. Grant P. R., Garson J. A., Tedder R. S., Chan P. K. S., Tam J. S., Sung J. J. Y. (2003). Detection of SARS coronavirus in plasma by real-time RT-PCR. N. Engl. J. Med. 349, 2468–2469. 10.1056/NEJM200312183492522
    1. Groves H. T., Cuthbertson L., James P., Moffatt M. F., Cox M. J., Tregoning J. S. (2018). Respiratory disease following viral lung infection alters the murine gut microbiota. Front. Immunol. 9:182. 10.3389/fimmu.2018.00182
    1. Gu L., Deng H., Ren Z., Zhao Y., Yu S., Guo Y., et al. . (2019). Dynamic changes in the microbiome and mucosal immune microenvironment of the lower respiratory tract by influenza virus infection. Front. Microbiol. 10:2491. 10.3389/fmicb.2019.02491
    1. Guan W.-J., Ni Z.-Y., Hu Y., Liang W.-H., Ou C.-Q., He J.-X., et al. (2020). Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720. 10.1056/NEJMoa2002032
    1. Hashimoto T., Perlot T., Rehman A., Trichereau J., Ishiguro H., Paolino M., et al. . (2012). ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487, 477–481. 10.1038/nature11228
    1. He Y., Wang Z., Li F., Shi Y. (2020). Public health might be endangered by possible prolonged discharge of SARS-CoV-2 in stool. J. Infect. 80, e18–e19. 10.1016/j.jinf.2020.02.031
    1. Hepworth M. R., Fung T. C., Masur S. H., Kelsen J. R., Mcconnell F. M., Dubrot J., et al. . (2015). Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 348, 1031–1035. 10.1126/science.aaa4812
    1. Hijawi B., Abdallat M., Sayaydeh A. (2012). Novel coronavirus infections in jordan, April 2012: epidemiological findings from a retrospective investigation. East Mediterr Health J. 19(Suppl 1):S12–S18. 10.26719/2013.19.supp1.S12
    1. Hoffmann M., Kleine-Weber H., Krüger N., Müller M., Drosten C., Pöhlmann S. (2020). The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv. 10.1101/2020.01.31.929042
    1. Hooper L. V., Littman D. R., Macpherson A. J. (2012). Interactions between the microbiota and the immune system. Science 336, 1268–1273. 10.1126/science.1223490
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. . (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506. 10.1016/S0140-6736(20)30183-5
    1. Ichinohe T., Pang I. K., Kumamoto Y., Peaper D. R., Ho J. H., Murray T. S., et al. . (2011). Microbiota regulates immune defense against respiratory tract influenza a virus infection. Proc. Natl. Acad. Sci. U.S.A. 108, 5354–5359. 10.1073/pnas.1019378108
    1. Jeong S. Y., Sung S. I., Sung J.-H., Ahn S. Y., Kang E.-S., Chang Y. S., et al. . (2017). MERS-CoV infection in a pregnant woman in Korea. J. Korean Med. Sci. 32, 1717–1720. 10.3346/jkms.2017.32.10.1717
    1. Kanne J. P. (2020). Chest CT findings in 2019 novel coronavirus (2019-nCoV) infections from Wuhan, China: key points for the radiologist. Radiology 295, 16–17. 10.1148/radiol.2020200241
    1. Kuba K., Imai Y., Rao S., Gao H., Guo F., Guan B., et al. . (2005). A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 11, 875–879. 10.1038/nm1267
    1. Kyo M., Nishioka K., Nakaya T., Kida Y., Tanabe Y., Ohshimo S., et al. . (2019). Unique patterns of lower respiratory tract microbiota are associated with inflammation and hospital mortality in acute respiratory distress syndrome. Respir. Res. 20:246. 10.1186/s12931-019-1203-y
    1. Lee K. (2020). Pneumonia associated with 2019 novel coronavirus: can computed tomographic findings help predict the prognosis of the disease? Korean J. Radiol. 21, 257–258. 10.3348/kjr.2020.0096
    1. Lee S. H. (2003). The SARS epidemic in hong kong. J. Epidemiol. Commun. Health 57, 652–654. 10.1136/jech.57.9.652
    1. Lee Y. K., Mazmanian S. K. (2010). Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330, 1768–1773. 10.1126/science.1195568
    1. Li F. (2016). Structure, function, and evolution of coronavirus spike proteins. Annu. Rev. Virol. 3, 237–261. 10.1146/annurev-virology-110615-042301
    1. Li Q., Guan X., Wu P., Wang X., Zhou L., Tong Y., et al. . (2020). Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382, 1199–1207. 10.1056/NEJMoa2001316
    1. Lievin-Le Moal V., Servin A. L. (2006). The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clin. Microbiol. Rev. 19, 315–337. 10.1128/CMR.19.2.315-337.2006
    1. Lingkong Z., Xuwei T., Wenhao Y., Jin W., Xin L., Zhisheng L. (2020). First case of neonate infected with novel coronavirus pneumonia in China. Chin. J. Pediatr. 58:E009. 10.3760/cma.j.issn.0578-1310.2020.0009
    1. Maeda N., Nakamura R., Hirose Y., Murosaki S., Yamamoto Y., Kase T., et al. . (2009). Oral administration of heat-killed lactobacillus plantarum L-137 enhances protection against influenza virus infection by stimulation of type I interferon production in mice. Int. Immunopharmacol. 9, 1122–1125. 10.1016/j.intimp.2009.04.015
    1. Malik A., El Masry K. M., Ravi M., Sayed F. (2016). Middle east respiratory syndrome coronavirus during pregnancy, Abu Dhabi, United Arab Emirates, 2013. Emerg. Infect. Dis. 22, 515–517. 10.3201/eid2203.151049
    1. Meyer N. J., Calfee C. S. (2017). Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome. Lancet Respir. Med. 5, 512–523. 10.1016/S2213-2600(17)30187-X
    1. Molyneaux P. L., Mallia P., Cox M. J., Footitt J., Willis-Owen S. A., Homola D., et al. . (2013). Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 188, 1224–1231. 10.1164/rccm.201302-0341OC
    1. Otter J. A., Donskey C., Yezli S., Douthwaite S., Goldenberg S. D., Weber D. J. (2016). Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination. J. Hosp. Infect. 92, 235–250. 10.1016/j.jhin.2015.08.027
    1. Panzer A. R., Lynch S. V., Langelier C., Christie J. D., McCauley K., Nelson M., et al. . (2018). Lung microbiota is related to smoking status and to development of acute respiratory distress syndrome in critically ill trauma patients. Am. J. Respir. Crit. Care Med. 197, 621–631. 10.1164/rccm.201702-0441OC
    1. Peiris J. S. M., Guan Y., Yuen K. Y. (2004). Severe acute respiratory syndrome. Nat. Med. 10, S88–S97. 10.1038/nm1143
    1. Rothe C., Schunk M., Sothmann P., Bretzel G., Froeschl G., Wallrauch C., et al. . (2020). Transmission of 2019-nCoV infection from an asymptomatic contact in Germany. N. Engl. J. Med. 382, 970–971. 10.1056/NEJMc2001468
    1. Round J. L., Lee S. M., Li J., Tran G., Jabri B., Chatila T. A., et al. . (2011). The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977. 10.1126/science.1206095
    1. Shek C. C., Ng P. C., Fung G. P. G., Cheng F. W. T., Chan P. K. S., Peiris M. J. S., et al. . (2003). Infants born to mothers with severe acute respiratory syndrome. Pediatrics 112:e254. 10.1542/peds.112.4.e254
    1. Shen Z., Xiao Y., Kang L., Ma W., Shi L., Zhang L., et al. . (2020). Genomic diversity of SARS-CoV-2 in coronavirus disease 2019 patients. Clin. Infect. Dis. 9:ciaa203. 10.1093/cid/ciaa203
    1. Smith P. M., Howitt M. R., Panikov N., Michaud M., Gallini C. A., Bohlooly -Y. M., et al. . (2013). The microbial metabolites, short-chain fatty acids, regulate colonic treg cell homeostasis. Science 341, 569–573. 10.1126/science.1241165
    1. Steed A. L., Christophi G. P., Kaiko G. E., Sun L., Goodwin V. M., Jain U., et al. . (2017). The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357, 498–502. 10.1126/science.aam5336
    1. Tang X., Wu C., Li X., Song Y., Yao X., Wu X., et al. (2020). On the origin and continuing evolution of SARS-CoV-2. Natl. Sci. Rev. 3:nwaa036 10.1093/nsr/nwaa036
    1. Tanoue T., Atarashi K., Honda K. (2016). Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295–309. 10.1038/nri.2016.36
    1. Thackray L. B., Handley S. A., Gorman M. J., Poddar S., Bagadia P., Briseño C. G., et al. . (2018). Oral antibiotic treatment of mice exacerbates the disease severity of multiple flavivirus infections. Cell. Rep. 22, 3440.e6–3453.e6. 10.1016/j.celrep.2018.03.001
    1. The Lancet (2020). Emerging understandings of 2019-nCoV. Lancet 395:311. 10.1016/S0140-6736(20)30186-0
    1. Trompette A., Gollwitzer E. S., Pattaroni C., Lopez-Mejia I. C., Riva E., Pernot J., et al. . (2018). Dietary fiber confers protection against flu by shaping Ly6c– patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity. 48, 992–1005.e8. 10.1016/j.immuni.2018.04.022
    1. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., et al. . (2020). Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323, 1061–1069. 10.1001/jama.2020.1585
    1. Wang H., Mao Y., Ju L., Zhang J., Liu Z., Zhou X., et al. . (2004). Detection and monitoring of SARS coronavirus in the plasma and peripheral blood lymphocytes of patients with severe acute respiratory syndrome. Clin. Chem. 50, 1237–1240. 10.1373/clinchem.2004.031237
    1. Wang J., Wang D., Chen G. C., Tao X. W., Zeng L. K. (2020). SARS-CoV-2 infection with gastrointestinal symptoms as the first manifestation in a neonate. Zhongguo Dang Dai Er Ke Za Zhi. 22, 211–214. 10.7499/j.issn.1008-8830.2020.03.006
    1. World Health Organization (2019). Coronavirus Disease. (accessed May 28, 2020).
    1. Wrapp D., Wang N., Corbett K. S., Goldsmith J. A., Hsieh C.-L., Abiona O., et al. . (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260–1263. 10.1126/science.abb2507
    1. Wu A., Peng Y., Huang B., Ding X., Wang X., Niu P., et al. . (2020). Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe. 27, 325–328. 10.1016/j.chom.2020.02.001
    1. Wu F., Zhao S., Yu B., Chen Y.-M., Wang W., Song Z.-G., et al. . (2020). A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269. 10.1038/s41586-020-2008-3
    1. Yip C. W., Hon C. C., Shi M., Lam T. T.-Y., Chow K. Y.-C., Zeng F., et al. . (2009). Phylogenetic perspectives on the epidemiology and origins of SARS and SARS-like coronaviruses. Infect. Genet. Evol. 9, 1185–1196. 10.1016/j.meegid.2009.09.015
    1. Young B. E., Ong S. W. X., Kalimuddin S., Low J. G., Tan S. Y., Loh J., et al. . (2020). Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 323, 1488–1494. 10.1001/jama.2020.3204
    1. Zeng H., Xu C., Fan J., Tang Y., Deng Q., Zhang W., et al. . (2020). Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA 23, 1848–1849. 10.1001/jama.2020.4861
    1. Zhang F. (2020). Washed Microbiota Transplantation for Patients With 2019-nCoV Infection. (accessed May 28, 2020).
    1. Zhang H., Kang Z., Gong H., Xu D., Wang J., Li Z., et al. (2020). The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. BioRxiv. 10.1101/2020.01.30.927806
    1. Zhao Y., Chen F., Wu W., Sun M., Bilotta A. J., Yao S., et al. . (2018). GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol. 11, 752–762. 10.1038/mi.2017.118
    1. Zhao Y., Zhao Z., Wang Y., Zhou Y., Ma Y., Zuo W. (2020). Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. BioRxiv. 10.1101/2020.01.26.919985
    1. Zhong N. S., Zheng B. J., Li Y. M., Poon L. L. M., Xie Z. H., Chan K. H., et al. . (2003). Epidemiology and cause of severe acute respiratory syndrome (SARS) in guangdong, people's republic of China, in February, 2003. Lancet 362, 1353–1358. 10.1016/S0140-6736(03)14630-2
    1. Zhou P., Yang X.-L., Wang X.-G., Hu B., Zhang L., Zhang W., et al. . (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273. 10.1038/s41586-020-2012-7

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