Document Type : Review Article


1 ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR,Tehran, Iran

2 Department of Cellular and Molecular Tehran Medical Sciences Branch,lslamic Azad University, Tehran, Iran



Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2), is a severe infection with respiratory and systemic
manifestations. This infectious disease has a complex course and manifests itself with
various clinical presentations, ranging from asymptomatic infection to a severe clinical
course. These variations in severity have raised the question of whether the genetic or
epigenetic variations have a role in COVID-19 susceptibility or severity, and that these
factors can be used to predict the disease course. A whole-genome sequencing performed
on 95 samples of SARS-CoV-2 identified 116 unique mutations, most of which were
missense and synonymous. Moreover, some studies have reported a relationship between
the COVID-19 severity and the genes ACE and TMPRSS2. The present review provides
an overview of different genes that have been found to be implicated or related to the
susceptibility to COVID-19 or its severity.


1. Abraham EP, Chain E. An enzyme from bacteria able to destroy
penicillin. Nature. 1940 Dec;146(3713):837-.
2. Aldred KJ, Kerns RJ, Osheroff N. Mechanism of quinolone
action and resistance. Biochemistry. 2014 Mar 18;53(10):1565-
3. Allen HK, Moe LA, Rodbumrer J, Gaarder A, Handelsman
J. Functional metagenomics reveals diverse β-lactamases in a
remote Alaskan soil. The ISME journal. 2009 Feb;3(2):243-51.
4. Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD.
Effect of antibiotic prescribing in primary care on antimicrobial
resistance in individual patients: systematic review and meta-
analysis. Bmj. 2010 May 18;340.
5. Benveniste R, Davies J. Aminoglycoside antibiotic-inactivating
enzymes in actinomycetes similar to those present in clinical
isolates of antibiotic-resistant bacteria. Proceedings of the
National Academy of Sciences. 1973 Aug 1;70(8):2276-80.
6. Fernández L, Hancock RE. Adaptive and mutational resistance:
role of porins and efflux pumps in drug resistance. Clinical
microbiology reviews. 2012 Oct;25(4):661-81.
7. Leclercq R. Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical
implications. Clinical Infectious Diseases. 2002 Feb 15;34(4):482-
8. Holmes AH, Moore LS, Sundsfjord A, Steinbakk M, Regmi S,
Karkey A, Guerin PJ, Piddock LJ. Understanding the mechanisms
and drivers of antimicrobial resistance. The Lancet. 2016 Jan
9. Miller WR, Munita JM, Arias CA. Mechanisms of antibiotic
resistance in enterococci. Expert review of anti-infective therapy.
2014 Oct 1;12(10):1221-36.
10. Nikaido H, Pagès JM. Broad-specificity efflux pumps and their
role in multidrug resistance of Gram-negative bacteria. FEMS
microbiology reviews. 2012 Mar 1;36(2):340-63.
11. Demple B, Amabile-Cuevas CF. ‘Multiple resistance mediated
by individual genetic loci. Multiple drug resistant bacteria.
Horizon Scientific Press, Wymondham, UK. 2003:61-80.
12. D’Costa VM, King CE, Kalan L, Morar M, Sung WW, Schwarz
C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB.
Antibiotic resistance is ancient. Nature. 2011 Sep;477(7365):457-
13. da SILVA KC, KNÖBL T, Moreno AM. Antimicrobial
resistance in veterinary medicine. Braz. j. vet. res. anim. sci.
14. Nisha AR. Antibiotic residues-a global health hazard.
Veterinary world. 2008 Dec 1;1(12):375.
15. Hao H, Cheng G, Iqbal Z, Ai X, Hussain HI, Huang L, Dai
M, Wang Y, Liu Z, Yuan Z. Benefits and risks of antimicrobial
use in food-producing animals. Frontiers in microbiology. 2014
Jun 12;5:288.
16. Weinstein RA. Controlling antimicrobial resistance in
hospitals: infection control and use of antibiotics. Emerging
infectious diseases. 2001 Mar;7(2):188.
17. Aarestrup FM. Occurrence of glycopeptide resistance among
Enterococcus faecium isolates from conventional and ecological
poultry farms. Microbial Drug Resistance. 1995;1(3):255-7.
18. Aarestrup FM, Jensen NE. Development of penicillin
resistance among Staphylococcus aureus isolated from bovine
mastitis in Denmark and other countries. Microbial Drug
Resistance. 1998;4(3):247-56.
19. Adrian PV, Thomson CJ, Klugman KP, Amyes SG. New gene
cassettes for trimethoprim resistance, dfr13, and streptomycin-
spectinomycin resistance, aadA4, inserted on a class 1 integron.
Antimicrobial agents and chemotherapy. 2000 Feb 1;44(2):355-
20. Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies
J, Handelsman J. Call of the wild: antibiotic resistance genes
in natural environments. Nature Reviews Microbiology. 2010
21. DiazGranados CA, Zimmer SM, Mitchel K, Jernigan
JA. Comparison of mortality associated with vancomycin-
resistant and vancomycin-susceptible enterococcal bloodstream
infections: a meta-analysis. Clinical infectious diseases. 2005 Aug
22. Nannini EC, Singh KV, Arias CA, Murray BE. In vivo
effects of cefazolin, daptomycin, and nafcillin in experimental
endocarditis with a methicillin-susceptible Staphylococcus aureus
strain showing an inoculum effect against cefazolin. Antimicrobial
agents and chemotherapy. 2013 Sep;57(9):4276-81.
23. Thomas CM, Nielsen KM. Mechanisms of, and barriers
to, horizontal gene transfer between bacteria. Nature reviews
microbiology. 2005 Sep;3(9):711-21.
24. Hollenbeck BL, Rice LB. Intrinsic and acquired resistance
mechanisms in enterococcus. Virulence. 2012 Aug 15;3(5):421-
25. Abraham EP, Chain E. An enzyme from bacteria able to
destroy penicillin. Nature. 1940 Dec;146(3713):837-.
26. Bush K, Jacoby GA. Updated functional classification of
β-lactamases. Antimicrobial agents and chemotherapy. 2010
27. Sirot D, Sirot J, Labia R, Morand A, Courvalin P, Darfeuille-
Michaud A, Perroux R, Cluzel R. Transferable resistance to
third-generation cephalosporins in clinical isolates of Klebsiella
pneumoniae: identification of CTX-1, a novel β-lactamase.
Journal of Antimicrobial Chemotherapy. 1987 Sep 1;20(3):323-
28. Jacobs C, Frère JM, Normark S. Cytosolic intermediates
for cell wall biosynthesis and degradation control inducible
β-lactam resistance in gram-negative bacteria. Cell. 1997 Mar
29. Pagès JM, James CE, Winterhalter M. The porin and the
permeating antibiotic: a selective diffusion barrier in Gram-
negative bacteria. Nature Reviews Microbiology. 2008
30. Hasdemir UO, Chevalier J, Nordmann P, Pagès JM. Detection
and prevalence of active drug efflux mechanism in various
multidrug-resistant Klebsiella pneumoniae strains from Turkey.
Journal of clinical microbiology. 2004 Jun;42(6):2701-6.
31. Adachi H, Ishiguro M, Imajoh S, Ohta T, Matsuzawa H.
Active-site residues of the transpeptidase domain of penicillin-
binding protein 2 from Escherichia coli: similarity in catalytic
mechanism to class A. beta.-lactamases. Biochemistry. 1992
32. Alekshun MN, Levy SB. The mar regulon: multiple resistance
to antibiotics and other toxic chemicals. Trends in microbiology.
1999 Oct 1;7(10):410-3.
33. Alonso A, Sanchez P, Martínez JL. Stenotrophomonas
maltophilia D457R contains a cluster of genes from gram-positive
bacteria involved in antibiotic and heavy metal resistance.
Antimicrobial agents and chemotherapy. 2000 Jul 1;44(7):1778-
34. Benveniste R, Davies J. Aminoglycoside antibiotic-
inactivating enzymes in actinomycetes similar to those present in
clinical isolates of antibiotic-resistant bacteria. Proceedings of the
National Academy of Sciences. 1973 Aug 1;70(8):2276-80.
35. Aminov RI, Garrigues-Jeanjean N, Mackie RI. Molecular
ecology of tetracycline resistance: development and validation
of primers for detection of tetracycline resistance genes encoding
ribosomal protection proteins. Applied and environmental
microbiology. 2001 Jan 1;67(1):22-32.
36. Atkinson BA, Abu-Al-Jaibat A, LeBlanc DJ. Antibiotic
resistance among enterococci isolated from clinical specimens
between 1953 and 1954. Antimicrobial agents and
chemotherapy. 1997 Jul;41(7):1598-600.
37. Batt AL, Snow DD, Aga DS. Occurrence of sulfonamide
antimicrobials in private water wells in Washington County,
Idaho, USA. Chemosphere. 2006 Sep 1;64(11):1963-71.
38. McMurry L, Petrucci RE, Levy SB. Active efflux of
tetracycline encoded by four genetically different tetracycline
resistance determinants in Escherichia coli. Proceedings of the
national academy of sciences. 1980 Jul 1;77(7):3974-7.
39. Dönhöfer A, Franckenberg S, Wickles S, Berninghausen O,
Beckmann R, Wilson DN. Structural basis for TetM-mediated
tetracycline resistance. Proceedings of the National Academy of
Sciences. 2012 Oct 16;109(42):16900-5.
40. Aldred KJ, Kerns RJ, Osheroff N. Mechanism of quinolone
action and resistance. Biochemistry. 2014 Mar 18;53(10):1565-74.
41. Bayer AS, Schneider T, Sahl HG. Mechanisms of daptomycin
resistance in Staphylococcus aureus: role of the cell membrane
and cell wall. Annals of the New York Academy of Sciences. 2013
42. Howden BP, Davies JK, Johnson PD, Stinear TP, Grayson
ML. Reduced vancomycin susceptibility in Staphylococcus
aureus, including vancomycin-intermediate and heterogeneous
vancomycin-intermediate strains: resistance mechanisms,
laboratory detection, and clinical implications. Clinical
microbiology reviews. 2010 Jan;23(1):99-139.
43. Watanabe Y, Cui L, Katayama Y, Kozue K, Hiramatsu K.
Impact of rpoB mutations on reduced vancomycin susceptibility
in Staphylococcus aureus. Journal of Clinical Microbiology. 2011
44. Tran TT, Panesso D, Mishra NN, Mileykovskaya E, Guan Z,
Munita JM, Reyes J, Diaz L, Weinstock GM, Murray BE, Shamoo
Y. Daptomycin-resistant Enterococcus faecalis diverts the
antibiotic molecule from the division septum and remodels cell
membrane phospholipids. MBio. 2013 Jul 23;4(4):e00281-13.
45. Silver S, Phung LT. Bacterial heavy metal resistance: new
surprises. Annual review of microbiology. 1996 Oct;50(1):753-
46. Witte W. Medical consequences of antibiotic use in agriculture.
47. Davies J. Inactivation of antibiotics and the dissemination of
resistance genes. Science. 1994 Apr 15;264(5157):375-82.