1921
Volume 103, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

The ongoing pandemic COVID-19, caused by SARS-CoV-2, has already resulted in more than 3 million cases and more than 200,000 deaths globally. Significant clinical presentations of COVID-19 include respiratory symptoms and pneumonia. In a minority of patients, extrapulmonary organs (central nervous system, eyes, heart, and gut) are affected, with detection of viral RNA in bodily secretions (stool, tears, and saliva). Infection of such extrapulmonary organs may serve as a reservoir for SARS-CoV-2, representing a potential source of viral shedding after the cessation of respiratory symptoms in recovered patients or in asymptomatic individuals. It is extremely important to understand this phenomenon, as individuals with intermittent virus shedding could be falsely identified as reinfected and may benefit from ongoing antiviral treatment. The potential of SARS-CoV-2 infection to rapidly disseminate and infect extrapulmonary organs is likely mediated through the nonstructural and accessory proteins of SARS-CoV-2, which act as ligands for host cells, and through evasion of host immune responses. The focus of this perspective is the extrapulmonary tissues affected by SARS-CoV-2 and the potential implications of their involvement for disease pathogenesis and the development of medical countermeasures.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Loading

Article metrics loading...

The graphs shown below represent data from March 2017
/content/journals/10.4269/ajtmh.20-0279
2020-05-13
2020-08-08
Loading full text...

Full text loading...

/deliver/fulltext/14761645/103/1/tpmd200279.html?itemId=/content/journals/10.4269/ajtmh.20-0279&mimeType=html&fmt=ahah

References

  1. Baig AM, Khaleeq A, Ali U, Syeda H, 2020. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 11: 995998.
    [Google Scholar]
  2. Sun X, Zhang X, Chen X, Chen L, Deng C, Zou X, Liu W, Yu H, 2020. The Infection Evidence of SARS-COV-2 in Ocular Surface: A Single-Center Cross-Sectional Study. Available at: https://www.medrxiv.org/content/10.1101/2020.02.26.20027938v1. Accessed May 5, 2020.
    [Google Scholar]
  3. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W, 2020. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA e203786. Available at: https://jamanetwork.com/journals/jama/fullarticle/2762997.
    [Google Scholar]
  4. Rothe C et al., 2020. Transmission of 2019-nCoV infection from an asymptomatic contact in Germany. N Engl J Med 382: 970971.
    [Google Scholar]
  5. Zhou X, Li Y, Li T, Zhang W, 2020. Follow-up of the asymptomatic patients with SARS-CoV-2 infection. Clin Microbiol Infect. Available at: https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30169-5/pdf.
    [Google Scholar]
  6. Bao L et al., 2020. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv. Available at: https://www.biorxiv.org/content/10.1101/2020.03.13.990226v2.
    [Google Scholar]
  7. Holappa M, Valjakka J, Vaajanen A, 2015. Angiotensin (1–7) and ACE2, “the hot spots” of renin-angiotensin system, detected in the human aqueous humor. Open Ophthalmol J 9: 2832.
    [Google Scholar]
  8. Senanayake P, Drazba J, Shadrach K, Milsted A, Rungger-Brandle E, Nishiyama K, Miura SI, Karnik S, Sears JE, Hollyfield JG, 2007. Angiotensin II and its receptor subtypes in the human retina. Invest Ophthalmol Vis Sci 48: 33013311.
    [Google Scholar]
  9. AnnRemington L, 2012. Clinical anatomy and physiology of the visual system. Remington LA, ed. Ocular Adnexa and Lacrimal System. Oxford, UK: Butterworth-Heinemann, 159181.
    [Google Scholar]
  10. Xia J, Tong J, Liu M, Shen Y, Guo D, 2020. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection. J Med Virol. Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25725.
    [Google Scholar]
  11. Wu P, Duan F, Luo C, Liu Q, Qu X, Liang L, Wu K, 2020. Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei province, China. JAMA Ophthalmol e201291. Available at: https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2764083.
    [Google Scholar]
  12. Yeo C, Kaushal S, Yeo D, 2020. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol 5: 335337.
    [Google Scholar]
  13. Hosoda T, Sakamoto M, Shimizu H, Okabe N, 2020. SARS-CoV-2 enterocolitis with persisting to excrete the virus for about two weeks after recovering from diarrhea: a case report. Infect Control Hosp Epidemiol 1: 14.
    [Google Scholar]
  14. Lodder W, de Roda Husman AM, 2020. SARS-CoV-2 in wastewater: potential health risk, but also data source. Lancet Gastroenterol Hepatol. Available at: https://www.thelancet.com/pdfs/journals/langas/PIIS2468-1253(20)30087-X.pdf.
    [Google Scholar]
  15. Mao L et al., 2020. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv. Available at: https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1.
    [Google Scholar]
  16. Moriguchi T et al., 2020. A first case of meningitis/encephalitis associated with SARS-coronavirus-2. Int J Infect Dis 94: 5558.
    [Google Scholar]
  17. Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, Liu C, Yang C, 2020. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. Available at: https://www.sciencedirect.com/science/article/pii/S0889159120303573?via%3Dihub.
    [Google Scholar]
  18. Rismanbaf A, Zarei S, 2020. Liver and kidney injuries in COVID-19 and their effects on drug therapy; a letter to editor. Arch Acad Emerg Med 8: e17.
    [Google Scholar]
  19. Chen T et al., 2020. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 368: m1091.
    [Google Scholar]
  20. Chan JF et al., 2020. Simulation of the clinical and pathological manifestations of coronavirus disease 2019 (COVID-19) in golden syrian hamster model: implications for disease pathogenesis and transmissibility. Clin Infect Dis. Available at: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa325/5811871.
    [Google Scholar]
  21. Guan WJ et al., 2020. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 382: 17081720.
    [Google Scholar]
  22. Kaye M, 2006. SARS-associated coronavirus replication in cell lines. Emerg Infect Dis 12: 128133.
    [Google Scholar]
  23. Chau TN et al., 2004. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases. Hepatology 39: 302310.
    [Google Scholar]
  24. Xu J et al., 2005. Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis. Clin Infect Dis 41: 10891096.
    [Google Scholar]
  25. Barker CF, Billingham RE, 1977. Immunologically privileged sites. Adv Immunol 25: 154.
    [Google Scholar]
  26. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC, 2006. CNS immune privilege: hiding in plain sight. Immunol Rev 213: 4865.
    [Google Scholar]
  27. Kalkeri R, Murthy KK, 2017. Zika virus reservoirs: implications for transmission, future outbreaks, drug vaccine development. F1000Res 6: 1850.
    [Google Scholar]
  28. Lan L, Xu D, Ye G, Xia C, Wang S, Li Y, Xu H, 2020. Positive RT-PCR test results in patients recovered from COVID-19. JAMA 323: 15021503.
    [Google Scholar]
  29. Hu Z et al., 2020. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci 63: 706711.
    [Google Scholar]
  30. Li J, Zhang L, Liu B, Song D, 2020. Case report: viral shedding for 60 Days in a woman with novel coronavirus disease (COVID-19). Am J Trop Med Hyg 102: 12101213.
    [Google Scholar]
  31. To KK et al., 2020. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 20: 565574.
    [Google Scholar]
  32. Gordon DE et al., 2020. A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential drug-repurposing. bioRxiv. Available at: https://www.biorxiv.org/content/10.1101/2020.03.22.002386v3.
    [Google Scholar]
  33. Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang M, 2020. Presumed asymptomatic carrier transmission of COVID-19. JAMA 323: 14061407.
    [Google Scholar]
  34. Mizumoto K, Kagaya K, Zarebski A, Chowell G, 2020. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the diamond princess cruise ship, Yokohama, Japan, 2020. Euro Surveill 25: 2000180.
    [Google Scholar]
  35. Nishiura H et al., 2020. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). Int J Infect Dis 94: 154155.
    [Google Scholar]
  36. Miura F, Matsuyama R, Nishiura H, 2018. Estimating the asymptomatic ratio of norovirus infection during foodborne outbreaks with laboratory testing in Japan. J Epidemiol 28: 382387.
    [Google Scholar]
  37. Mizumoto K, Kobayashi T, Chowell G, 2018. Transmission potential of modified measles during an outbreak, Japan, March-May 2018. Euro Surveill 23: 1800239.
    [Google Scholar]
  38. Goh KJ, Choong MC, Cheong EH, Kalimuddin S, Duu Wen S, Phua GC, Chan KS, Haja Mohideen S, 2020. Rapid progression to acute respiratory distress syndrome: review of current understanding of critical illness from COVID-19 infection. Ann Acad Med Singapore 49: 19.
    [Google Scholar]
  39. Seah I, Agrawal R, 2020. Can the coronavirus disease 2019 (COVID-19) affect the eyes? A review of coronaviruses and ocular implications in humans and animals. Ocul Immunol Inflamm 28: 391395.
    [Google Scholar]
  40. Zhang C, Shi L, Wang FS, 2020. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 5: 428430.
    [Google Scholar]
  41. Xu L, Liu J, Lu M, Yang D, Zheng X, 2020. Liver injury during highly pathogenic human coronavirus infections. Liver Int 40: 9981004.
    [Google Scholar]
  42. Li YC, Bai WZ, Hashikawa T, 2020. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25728.
    [Google Scholar]
  43. Glass WG, Subbarao K, Murphy B, Murphy PM, 2004. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 173: 40304039.
    [Google Scholar]
  44. Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK, McCray PB Jr., 2016. Middle east respiratory syndrome coronavirus causes multiple organ damage and Lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis 213: 712722.
    [Google Scholar]
  45. Talbot PJ, Ekande S, Cashman NR, Mounir S, Stewart JN, 1993. Neurotropism of human coronavirus 229E. Adv Exp Med Biol 342: 339346.
    [Google Scholar]
  46. Dube M, Le Coupanec A, Wong AHM, Rini JM, Desforges M, Talbot PJ, 2018. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J Virol 92: e00404-18.
    [Google Scholar]
  47. Hirano N, Murakami T, Taguchi F, Fujiwara K, Matumoto M, 1981. Comparison of mouse hepatitis virus strains for pathogenicity in weanling mice infected by various routes. Arch Virol 70: 6973.
    [Google Scholar]
  48. Uzelac-Keserovic B, Spasic P, Bojanic N, Dimitrijevic J, Lako B, Lepsanovic Z, Kuljic-Kapulica N, Vasic D, Apostolov K, 1999. Isolation of a coronavirus from kidney biopsies of endemic Balkan nephropathy patients. Nephron 81: 141145.
    [Google Scholar]
  49. Bouvier M et al., 2018. Species-specific clinical characteristics of human coronavirus infection among otherwise healthy adolescents and adults. Influenza Other Respir Viruses 12: 299303.
    [Google Scholar]
  50. Kamitani W, Narayanan K, Huang C, Lokugamage K, Ikegami T, Ito N, Kubo H, Makino S, 2006. Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc Natl Acad Sci USA 103: 1288512890.
    [Google Scholar]
  51. Narayanan K, Huang C, Lokugamage K, Kamitani W, Ikegami T, Tseng CT, Makino S, 2008. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells. J Virol 82: 44714479.
    [Google Scholar]
  52. Barretto N, Jukneliene D, Ratia K, Chen Z, Mesecar AD, Baker SC, 2005. The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol 79: 1518915198.
    [Google Scholar]
  53. Fehr AR, Channappanavar R, Jankevicius G, Fett C, Zhao J, Athmer J, Meyerholz DK, Ahel I, Perlman S, 2016. The conserved coronavirus macrodomain promotes virulence and suppresses the innate immune response during severe acute respiratory syndrome coronavirus infection. mBio 7: e01721.
    [Google Scholar]
  54. Menachery VD, Yount BL Jr., Josset L, Gralinski LE, Scobey T, Agnihothram S, Katze MG, Baric RS, 2014. Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2’-o-methyltransferase activity. J Virol 88: 42514264.
    [Google Scholar]
  55. Minakshi R, Padhan K, Rani M, Khan N, Ahmad F, Jameel S, 2009. The SARS coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor. PLoS One 4: e8342.
    [Google Scholar]
  56. Frieman M, Heise M, Baric R, 2008. SARS coronavirus and innate immunity. Virus Res 133: 101112.
    [Google Scholar]
  57. Shi CS, Qi HY, Boularan C, Huang NN, Abu-Asab M, Shelhamer JH, Kehrl JH, 2014. SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J Immunol 193: 30803089.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.20-0279
Loading
/content/journals/10.4269/ajtmh.20-0279
Loading

Data & Media loading...

  • Received : 11 Apr 2020
  • Accepted : 05 May 2020
  • Published online : 13 May 2020

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error