Γενετική βάση της ετερογένειας της συμπτωματολογίας του ανθρώπου-ξενιστή στη νόσο CoViD-19
Keywords:
Νέος κορωνοϊός, SARS-CoV-2, COVID-19, γενετική προδιάθεση
Abstract
Ο πανδημικός νέος κορωνοϊός (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) προκαλεί ευρύ φάσμα κλινικών εκδηλώσεων της νόσου COVID-19 (coronavirus disease of 2019), οι οποίες κυμαίνονται από ασυμπτωματικές ή ήπια συμπτωματικές λοιμώξεις, στην πλειονότητα των περιπτώσεων, έως τη σοβαρή πνευμονία, την αναπνευστική ανεπάρκεια και τον θάνατο. Το εύλογο λοιπόν ερώτημα που προκύπτει είναι εάν γενετικοί παράγοντες του ανθρώπου-ξενιστή μπορεί να ευθύνονται για τους διαφορετικούς αυτούς «φαινότυπους». Εδώ παρουσιάζουμε, με κριτική ματιά, τις συσχετίσεις μεταξύ γενετικών παραλλαγών ασθενών και κλινικής νόσου ή ευαισθησίας στη λοίμωξη με τον ιό που έχουν αναφερθεί στη βιβλιογραφία μέχρι σήμερα. Οι καθοριστικοί παράγοντες που διαφοροποιούν τη σοβαρότητα της νόσου περιλαμβάνουν κυρίως συστατικά της ανοσοαπόκρισης στον ιό, ενώ παράγοντες που διαφοροποιούν τον κίνδυνο προσβολής από τον ιό περιλαμβάνουν κυρίως γονίδια που σχετίζονται με τα αρχικά στάδια της μόλυνσης, δηλαδή την πρόσδεση του ιού σε κυτταρικούς υποδοχείς και την είσοδό του στα κύτταρα. Η ταυτοποίηση των γενετικών παραγόντων που καθορίζουν την σοβαρότητα της νόσου COVID-19 και την ευαισθησία στη λοίμωξη με τον ιό SARS-CoV-2 θα επέτρεπε τη διαστρωμάτωση ανάλογα με τον σχετικό κίνδυνο, έτσι ώστε τα άτομα που διατρέχουν υψηλό κίνδυνο να έχουν προτεραιότητα, παραδείγματος χάριν για ανοσοποίηση, εάν ή όταν αναπτυχθεί ένα ασφαλές και αποτελεσματικό εμβόλιο, ενώ θα μπορούσε επίσης να καθοδηγήσει εξατομικευμένες θεραπευτικές προσεγγίσεις. Επιπλέον, η γνώση αυτή έχει ήδη αρχίσει να παρέχει ενδείξεις που ερμηνεύουν, τουλάχιστον εν μέρει, τις τρέχουσες επιδημιολογικές παρατηρήσεις σχετικά με την τυπικά πιο σοβαρή πορεία της νόσου σε άνδρες μεγαλύτερης ηλικίας και, αντίστροφα, τη συνήθη καλοήθη πορεία στα παιδιά.
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50. Jaillon S, Berthenet K, Garlanda C. Sexual Dimorphism in Innate Immunity. Clin Rev Allergy Immunol 2019; 56(3): 308-321.
51. Klein SL, Marriott I, Fish EN. Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg 2015; 109(1): 9–15.
52. Souyris M, Mejía JE, Chaumeil J, Guéry J-C. Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation. Semin Immunopathol 2019; 41(2): 153-164.
53. Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, et al. Estrogens and autoimmune diseases. Ann N Y Acad Sci 2006; 1089: 538–547.
2. Grasselli G, Zangrillo A, Zanella A, et al; COVID-19 Lombardy ICU Network. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA 2020; 323(16): 1574-1581.
3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan China: a retrospective cohort study. Lancet 2020; 395: 1054–62.
4. Nakeshbandi M, Maini R, Daniel P, et al. The impact of obesity on COVID-19 complications: a retrospective cohort study. Int J Obes (Lond) 2020. doi: 10.1038/s41366-020-0648-x
5. Godri Pollitt KJ, Peccia J, Ko AI, et al. COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission. Hum Genomics 2020; 14(1): 17.
6. Ellinghaus D, Degenhardt F, Bujanda L, et al. Genomewide association study of severe COVID-19 with respiratory failure. N Engl J Med 2020. doi:10.1056/NEJMoa2020283.
7. Vuille-dit-Bille RN, Camargo SM, Emmenegger L, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids 2015; 47: 693-705.
8. Kuba K, Imai Y, Ohto-Nakanishi T, Penninger JM. Trilogy of ACE2: a pepti- dase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacol Ther 2010; 128: 119-128.
9. Allen SJ, Crown SE, Handel TM. Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 2007; 25: 787-820.
10. Wein AN, McMaster SR, Takamura S, et al. CXCR6 regulates localization of tis- sue-resident memory CD8 T cells to the airways. J Exp Med 2019; 216: 2748-2762.
11. Hickey MJ, Held KS, Baum E, Gao JL, Murphy PM, Lane TE. CCR1 deficiency increases susceptibility to fatal coronavirus infection of the central nervous system. Viral Immunol 2007; 20: 599-608.
12. Zeberg H, Pääbo S. The major genetic risk factor for severe COVID-19 is inherited from Neandertals. bioRxiv 2020.07.03.186296; doi: https://doi.org/10.1101/2020.07.03.186296
13. COVID-19 Host Genetics Initiative. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur J Hum Genet 2020; 28: 715-718.
14. Nguyen A, David JK, Maden SK, et al. Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2. J Virol 2020; 94(13): e00510-e00520.
15. Lin M, Tseng H, Trejaut JA, et al. Association of HLA class I with severe acute respiratory syndrome coronavirus infection. BMC Med Genet 2003; 4 (9). https://doi.org/10.1186/1471-2350-4-9
16. Wang F, Huang S, Gao H, et al. Initial Whole Genome Sequencing and Analysis of the Host Genetic Contribution to COVID-19 Severity and Susceptibility. medRxiv 2020.06.09.20126607; doi: https://doi.org/10.1101/2020.06.09.20126607
17. Cheng Y, Cheng G, Chui CH, et al. ABO blood group and susceptibility to severe acute respiratory syndrome. JAMA 2005; 293: 1450-1451.
18. Zhao J, Yang Y, Huang H, et al. Relationship between the ABO Blood Group and the COVID-19 Susceptibility. Clin Infect Dis 2020; ciaa1150. doi:10.1093/cid/ciaa1150
19. Wu Y, Feng Z, Li P, Yu Q. Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19. Clin Chim Acta 2020; 509: 220-223.
20. Breiman A, Ruvën-Clouet N, Le Pendu J. Harnessing the natural anti-glycan im- mune response to limit the transmission of enveloped viruses such as SARS-CoV-2. PLoS Pathog 2020; 16(5): e1008556.
21. Comuzzie AG, Cole SA, Laston SL, et al. Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PLoS One 2012; 7(12): e51954.
22. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol 2020; 10.1002/jmv.25948. doi:10.1002/jmv.25948
23. Naitza S, Porcu E, Steri M, et al. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. PLoS Genet 2012; 8(1): e1002480. doi:10.1371/journal.pgen.1002480
24. Franchini M, Crestani S, Frattini F, Sissa C, Bonfanti C. ABO blood group and von Willebrand factor: biological implications. Clin Chem Lab Med 2014; 52: 1273-1276.
25. Murray GP, Post SR, Post GR. ABO blood group is a determinant of von Willebrand factor protein levels in human pulmonary endothelial cells. J Clin Pathol 2020; 73: 347-349.
26. Zietz M, Tatonetti NP. Testing the association between blood type and COVID-19 infection, intubation, and death. Preprint. medRxiv 2020; 2020.04.08.20058073. doi:10.1101/2020.04.08.20058073
27. Everitt AR, Clare S, Pertel T, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012; 484(7395): 519-523.
28. Thevarajan I, Nguyen THO, Koutsakos M, et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med 2020; 26(4): 453-455.
29. Wang Z, Zhang A, Wan Y, Liu X, Qiu C, Xi X, et al. Early hypercytokinemia is associated with interferon-induced transmembrane protein-3 dysfunction and predictive of fatal H7N9 infection. PNAS 2014; 111 (2): 769-774.
30. Atkins JL, Masoli JAH, Delgado J, et al. Preexisting Comorbidities Predicting COVID-19 and Mortality in the UK Biobank Community Cohort. J Gerontol A Biol Sci Med Sci 2020; glaa183. doi:10.1093/gerona/glaa183
31. Kuo CL, Pilling LC, Atkins JL, Kuchel GA, Melzer D. ApoE e2 and aging-related outcomes in 379,000 UK Biobank participants. Aging (Albany NY) 2020; 12(12): 12222-12233. doi:10.18632/aging.103405
32. Kuo CL, Pilling LC, Atkins JL, et al. APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort. J Gerontol A Biol Sci Med Sci 2020; glaa131. doi:10.1093/gerona/glaa131
33. Tudorache IF, Trusca VG, Gafencu AV. Apolipoprotein E - A multifunctional protein with implications in various pathologies as a result of its structural features. Comput Struct Biotechnol J 2017; 15: 359–365.
34. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen 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(2): 271–280.
35. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020. https:// doi.org/10.1007/s11684-020-0754-0.
36. Hou Y, Zhao J, Martin W, et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med 2020; 18(1): 216. doi:10.1186/s12916-020-01673-z
37. Stopsack KH, Mucci LA, Antonarakis ES, Nelson PS, Kantoff PW. TMPRSS2 and COVID-19: serendipity or opportunity for intervention? Cancer Discov 2020; 10(6): 779–782.
38. Yu J, Ouyang W, Chua MLK, Xie C. SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan. China JAMA Oncol 2020. https://doi.org/10.1001/jamaoncol.2020.0980.
39. Schuler A, Habermann C, Plosa J, et al. Age-related expression of SARS-CoV- 2 primining protease TMPRSS2 in the developing lung. 2020. bioRxiv 2020.05.22.111187; doi: https://doi.org/10.1101/2020.05.22.111187
40. Mostafavi H, Berisa T, Day FR, Perry JRB, Przeworski M, Pickrell JK. Identifying genetic variants that affect viability in large cohorts. PLoS Biol 2017; 15(9): e2002458.
41. Asselta R, Paraboschi EM, Mantovani A, Duga S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging (Albany NY) 2020; 12(11): 10087-10098.
42. Benetti E, Tita R, Spiga O, et al. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population. Eur J Hum Genet 2020; 1-13. doi:10.1038/s41431-020-0691-z
43. van der Made CI, Simons A, Schuurs-Hoeijmakers J, et al. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA 2020; e2013719. doi:10.1001/jama.2020.13719
44. Casanova J-L, Abel L, Quintana-Murci L. Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu Rev Immunol 2011; 29(1): 447-491.
45. Cervantes-Barragan L, Züst R, Weber F, et al. Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon. Blood 2007; 109(3): 1131-1137.
46. Moreno-Eutimio MA, López-Macías C, Pastelin-Palacios R. Bioinformatic analysis and identification of single-stranded RNA sequences recognized by TLR7/8 in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes. Microbes Infect 2020; 22(4-5): 226-229.
47. Channappanavar R, Fehr AR, Zheng J, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest 2019; 129(9): 3625-3639.
48. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020; 181(5): 1036-1045.
49. Schurz H, Salie M, Tromp G, Hoal EG, Kinnear CJ, Möller M. The X chromosome and sex-specific effects in infectious disease susceptibility. Hum Genomics 2019; 13(1): 2. doi:10.1186/s40246-018-0185-z
50. Jaillon S, Berthenet K, Garlanda C. Sexual Dimorphism in Innate Immunity. Clin Rev Allergy Immunol 2019; 56(3): 308-321.
51. Klein SL, Marriott I, Fish EN. Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg 2015; 109(1): 9–15.
52. Souyris M, Mejía JE, Chaumeil J, Guéry J-C. Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation. Semin Immunopathol 2019; 41(2): 153-164.
53. Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, et al. Estrogens and autoimmune diseases. Ann N Y Acad Sci 2006; 1089: 538–547.
