Where Do We Go from Here? Reflections on the Challenges and Possibilities of Defeating the COVID-19 Pandemic

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Sarah Crawford


Having recently made the evolutionary transition from bats to humans, the novel Coronavirus SARS-Cov-2 has single-handedly created a defining moment in human history as the world reluctantly embraces a new paradigm in which the devastating effects of rapidly emerging diseases underscore the fragility of human life. The purpose of this review is to take a broad-spectrum view of the challenges that lie ahead in defeating this ongoing pandemic. In the absence of a complete understanding of the SARS-CoV-2 virus and its pathogenic potential, the accomplishments of modern medicine in the molecular age, nevertheless, allow unprecedented insight into fine-tuned molecular mechanisms of infection and our increasing ability to monitor and assess this disease and its global consequences. This review attempts to define the virulence mechanisms and pathophysiological consequences of the SARS-Cov-2 virus that, based on our current understanding, will most likely respond to preventive and therapeutic approaches.

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CRAWFORD, Sarah. Where Do We Go from Here? Reflections on the Challenges and Possibilities of Defeating the COVID-19 Pandemic. Medical Research Archives, [S.l.], v. 8, n. 9, sep. 2020. ISSN 2375-1924. Available at: <https://journals.ke-i.org/mra/article/view/2219>. Date accessed: 27 oct. 2020. doi: https://doi.org/10.18103/mra.v8i9.2219.


1. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive care medicine. 2020 Apr;46(4):586-90.
2. Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, Hengartner N, Giorgi EE, Bhattacharya T, Foley B, Hastie KM. Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell. 2020 Jul 3.
3. Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, Yuen KY. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerging microbes & infections. 2020 Jan 1;9(1):221-36.
4. van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus AD, Haagmans BL, Gorbalenya AE, Snijder EJ, Fouchier RA. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio. 2012 Dec 31;3(6).
5. O’Brien TR, Thomas DL, Jackson SS, Prokunina-Olsson L, Donnelly RP, Hartmann R. Weak induction of interferon expression by SARS-CoV-2 supports clinical trials of interferon lambda to treat early COVID-19. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2020 Apr 17.
6. Kindler E, Thiel V, Weber F. Interaction of SARS and MERS coronaviruses with the antiviral interferon response. In Advances in virus research 2016 Jan 1 (Vol. 96, pp. 219-243). Academic Press.
7. Hu Y, Li W, Gao T, Cui Y, Jin Y, Li P, Ma Q, Liu X, Cao C. The severe acute respiratory syndrome coronavirus nucleocapsid inhibits type I interferon production by interfering with TRIM25-mediated RIG-I ubiquitination. Journal of virology. 2017 Apr 15;91(8).
8. Hu Y, Li W, Gao T, Cui Y, Jin Y, Li P, Ma Q, Liu X, Cao C. SARS coronavirus nucleocapsid inhibits type I interferon production by interfering with TRIM25-mediated RIG-I ubiquitination. Journal of Virology. 2017 Feb 1.
9. Chen F, Chan KH, Jiang Y, Kao RY, Lu HT, Fan KW, Cheng VC, Tsui WH, Hung IF, Lee TS, Guan Y. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. Journal of Clinical Virology. 2004 Sep 1;31(1):69-75.
10. Totura AL, Baric RS. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Current opinion in virology. 2012 Jun 1;2(3):264-75.
11. Dominguez SR, Travanty EA, Qian Z, Mason RJ. Human coronavirus HKU1 infection of primary human type II alveolar epithelial cells: cytopathic effects and innate immune response. PLoS One. 2013 Jul 24;8(7):e70129.
12. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020 Mar 1;38(1):1-9.
13. Centers for Disease Control and Prevention (CDC. Prevalence of IgG antibody to SARS-associated coronavirus in animal traders--Guangdong Province, China, 2003. MMWR. Morbidity and mortality weekly report. 2003 Oct 17;52(41):986.
14. Totura AL, Baric RS. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Current opinion in virology. 2012 Jun 1;2(3):264-75.
15. De Wit E, Van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology. 2016 Aug;14(8):523.
16. Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nature medicine. 2007 May;13(5):543-51.
17. Law HK, Cheung CY, Sia SF, Chan YO, Peiris JM, Lau YL. Toll-like receptors, chemokine receptors and death receptor ligands responses in SARS coronavirus infected human monocyte derived dendritic cells. BMC immunology. 2009 Dec 1;10(1):35.
18. Lucas K, Maes M. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Molecular neurobiology. 2013 Aug 1;48(1):190-204.
19. Rincon M, Irvin CG. Role of IL-6 in asthma and other inflammatory pulmonary diseases. International journal of biological sciences. 2012;8(9):1281.
20. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, Men D, Huang Q, Liu Y, Yang B, Ding J. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clinical Infectious Diseases. 2020 Apr 17.
21. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, Yuan Z. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Frontiers in Immunology. 2020 May 1;11:827.
22. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis GV, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 2004 Jun;203(2):631-7.
23. Tan YJ, Lim SG, Hong W. Understanding the accessory viral proteins unique to the severe acute respiratory syndrome (SARS) coronavirus. Antiviral research. 2006 Nov 1;72(2):78-88.
24. Shi CS, Nabar NR, Huang NN, Kehrl JH. SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell death discovery. 2019 Jun 5;5(1):1-2.
25. Yang M. Cell pyroptosis, a potential pathogenic mechanism of 2019-nCoV infection. Available at SSRN 3527420. 2020.
26. Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools. Virologica Sinica. 2020 Mar 3:1-6.
27. Deftereos SG, Siasos G, Giannopoulos G, Vrachatis DA, Angelidis C, Giotaki SG, Gargalianos P, Giamarellou H, Gogos C, Daikos G, Lazanas M. The GReek study in the Effects of Colchicine in COvid-19 complications prevention (GRECCO-19 study): rationale and study design. Hellenic Journal of Cardiology. 2020 Apr 3.
28. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nature Reviews Immunology. 2020 May 6:1-8.
29. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across Speciality Collaboration. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet (London, England). 2020 Mar 28;395(10229):1033.
30. Hanley B, Lucas SB, Youd E, Swift B, Osborn M. Autopsy in suspected COVID-19 cases. Journal of clinical pathology. 2020 May 1;73(5):239-42.
31. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, Fan Y, Zheng C. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. The Lancet Infectious Diseases. 2020 Feb 24.
32. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA cardiology. 2020 Mar 27.
33. Garg S. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 States, March 1–30, 2020. MMWR. Morbidity and mortality weekly report. 2020;69.
34. Ritchie AI, Singanayagam A. Immunosuppression for hyperinflammation in COVID-19: a double-edged sword? The Lancet. 2020 Apr 4;395(10230):1111.
35. Plett PA, Gardner EM, Murasko DM. Age-related changes in interferon-α/β receptor expression, binding, and induction of apoptosis in natural killer cells from C57BL/6 mice. Mechanisms of ageing and development. 2000 Sep 29;118(3):129-44.
36. Ludvigsson JF. Systematic review of COVID‐19 in children shows milder cases and a better prognosis than adults. Acta Paediatrica. 2020 Jun;109(6):1088-95.
37. She J, Liu L, Liu W. COVID‐19 epidemic: disease characteristics in children. Journal of medical virology. 2020 Mar 31.
38. Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv. 2020 Jan 1.
39. Franklin R, Young A, Neumann B, Fernandez R, Joannides A, Reyahi A, Modis Y. Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses: preliminary evidence that MMR vaccine might provide protection against COVID-19. medRxiv. 2020 Jan 1.
40. Salman S, Salem ML. Routine childhood immunization may protect against COVID-19. Medical hypotheses. 2020 Jul;140:109689.
41. Berg MK, Yu Q, Salvador CE, Melani I, Kitayama S. Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. Medrxiv. 2020 Jan 1.
42. Escobar LE, Molina-Cruz A, and Barillas-Mury M. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19). PNAS first published July 9, 2020 https://doi.org/10.1073/pnas.2008410117
43. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LF. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology. 2020 Apr 28:1-2.
44. Ray A, Chakraborty K, Ray P. Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of inflammation. Frontiers in cellular and infection microbiology. 2013 Sep 18;3:52.
45. Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. 2020 Jan 1.
46. Perricone C, Triggianese P, Bartoloni E, Cafaro G, Bonifacio AF, Bursi R, Perricone R, Gerli R. The anti-viral facet of anti-rheumatic drugs: lessons from COVID-19. Journal of Autoimmunity. 2020 Apr 17:102468.
47. Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S, Van Hemelrijck M. Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence. ecancermedicalscience. 2020;14.
48. Li F, Michelson AP, Foraker R, Payne PR. Signaling network analysis and drug repurposing for COVID-19 treatment based on transcriptional response of lung host cells. arXiv preprint arXiv:2006.01226. 2020 Jun 1.
49. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020 Apr 29.
50. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, Liao X, Gu Y, Cai Q, Yang Y, Shen C. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering. 2020 Mar 18.
51. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases. 2020 Mar 9.
52. Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, Brar I, Alangaden GJ, Ramesh MS, McKinnon JE, O’Neill W. Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. International Journal of Infectious Diseases. 2020 Jul 2.
53. Guastalegname M, Vallone A. Could chloroquine/hydroxychloroquine be harmful in coronavirus disease 2019 (COVID-19) treatment? Clinical Infectious Diseases. 2020 Mar 24.
54. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across Speciality Collaboration. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet (London, England). 2020 Mar 28;395(10229):1033.
55. Le TT, Andreadakis Z, Kumar A, Roman RG, Tollefsen S, Saville M, Mayhew S. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020 May;19(5):305-6.
56. Bottazzi ME, Strych U, Hotez PJ, Corry DB. Coronavirus Vaccine-Associated Lung Lindsley AW, Schwartz JT, Rothenberg ME. Eosinophil responses during COVID-19 infections and coronavirus vaccination. Journal of Allergy and Clinical Immunology. 2020 Apr 25.Immunopathology-What Is The Significance? Microbes and Infection. 2020 Jun 26.
57. Tseng CT, Sbrana E, Iwata-Yoshikawa N, Newman PC, Garron T, Atmar RL, Peters CJ, Couch RB. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PloS one. 2012 Apr 20;7(4):e35421.
58. Yasui F, Kai C, Kitabatake M, Inoue S, Yoneda M, Yokochi S, Kase R, Sekiguchi S, Morita K, Hishima T, Suzuki H. Prior immunization with severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) nucleocapsid protein causes severe pneumonia in mice infected with SARS-CoV. The Journal of Immunology. 2008 Nov 1;181(9):6337-48.
59. Roberts A, Lamirande EW, Vogel L, Jackson JP, Paddock CD, Guarner J, Zaki SR, Sheahan T, Baric R, Subbarao K. Animal models and vaccines for SARS-CoV infection. Virus research. 2008 Apr 1;133(1):20-32.
60. Jackson AC, SenGupta SK, Smith JF. Pathogenesis of Venezuelan equine encephalitis virus infection in mice and hamsters. Veterinary pathology. 1991 Sep;28(5):410-8.
61. Jiang S, He Y, Liu S. SARS vaccine development. Emerging infectious diseases. 2005 J Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, Tang H, Nishiura K, Peng J, Tan Z, Wu T. Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI insight. 2019 Feb 21;4(4).ul;11(7):1016.
62. Jaume M, Yip MS, Cheung CY, Leung HL, Li PH, Kien F, Dutry I, Callendret B, Escriou N, Altmeyer R, Nal B. Anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a pH-and cysteine protease-independent FcγR pathway. Journal of virology. 2011 Oct 15;85(20):10582-97.
63. Liu WJ, Zhao M, Liu K, Xu K, Wong G, Tan W, Gao GF. T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV. Antiviral research. 2017 Jan 1;137:82-9 Huang J, Ma R, Wu CY. Immunization with SARS-CoV S DNA vaccine generates memory CD4+ and CD8+ T cell immune responses. Vaccine. 2006 Jun 5;24(23):4905-13.2.
64. Wang YD, Sin WY, Xu GB, Yang HH, Wong TY, Pang XW, He XY, Zhang HG, Ng JN, Cheng CS, Yu J. T-cell epitopes in severe acute respiratory syndrome (SARS) coronavirus spike protein elicit a specific T-cell immune response in patients who recover from SARS. Journal of virology. 2004 Jun 1;78(11):5612-8.
65. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia. Emerging microbes & infections. 2020 Jan 1;9(1):727-32.
66. Wen W, Su W, Tang H, Le W, Zhang X, Zheng Y, Liu X, Xie L, Li J, Ye J, Dong L. Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell discovery. 2020 May 4;6(1):1-8.
67. Ahmed SF, Quadeer AA, McKay MR. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses. 2020 Mar;12(3):254

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