Skip to main content
NCBI home page
Wiley - PMC COVID-19 Collection logoLink to Wiley - PMC COVID-19 Collection
. 2022 May 31;94(9):4088–4096. doi: 10.1002/jmv.27849

Individual genetic variability mainly of Proinflammatory cytokines, cytokine receptors, and toll‐like receptors dictates pathophysiology of COVID‐19 disease

Mohammad Kazem Vakil 1, Yaser Mansoori 1, Ghaidaa Raheem Lateef Al‐Awsi 2,3, Ali Hosseinipour 4, Samaneh Ahsant 1, Sedigheh Ahmadi 1, Mohammad Ekrahi 1, Zahra Montaseri 5, Babak Pezeshki 1, Poopak Mohaghegh 6, Mojtaba Sohrabpour 1, Maryam Bahmanyar 6, Abdolreza Daraei 7, Tahereh Dadkhah Jouybari 8, Alireza Tavassoli 9,✉, Abdolmajid Ghasemian 1,✉
PMCID: PMC9348290  PMID: 35538614

Abstract

Innate and acquired immunity responses are crucial for viral infection elimination. However, genetic variations in coding genes may exacerbate the inflammation or initiate devastating cytokine storms which poses severe respiratory conditions in coronavirus disease‐19 (COVID‐19). Host genetic variations in particular those related to the immune responses determine the patients' susceptibility and COVID‐19 severity and pathophysiology. Gene polymorphisms such as single nucleotide polymorphisms (SNPs) of interferons, TNF, IL1, IL4, IL6, IL7, IL10, and IL17 predispose patients to the severe form of COVID‐19 or severe acute respiratory syndrome coronavirus‐2 (SARS‐COV‐2). These variations mainly alter the gene expression and cause a severe response by B cells, T cells, monocytes, neutrophils, and natural killer cells participating in a cytokine storm. Moreover, cytokines and chemokines SNPs are associated with the severity of COVID‐19 and clinical outcomes depending on the corresponding effect. Additionally, genetic variations in genes encoding toll‐like receptors (TLRs) mainly TLR3, TLR7, and TLR9 have been related to the COVID‐19 severe respiratory symptoms. The specific relation of these mutations with the novel variants of concern (VOCs) infection remains to be elucidated. Genetic variations mainly within genes encoding proinflammatory cytokines, cytokine receptors, and TLRs predispose patients to COVID‐19 disease severity. Understanding host immune gene variations associated with the SARS‐COV‐2 infection opens insights to control the pathophysiology of emerging viral infections.

Keywords: coronavirus disease‐19, cytokines, genetic variations, immunity, toll‐like receptors

1. INTRODUCTION

In December 2019, the first outbreak of a pneumonia‐like disease with unknown etiology was reported in Wuhan, China. 1 Chinese authorities primary recognition announced that the pathogen responsible for this disease was a novel coronavirus (2019‐nCoV) or COVID‐19. 2 This coronavirus was called “severe acute respiratory syndrome coronavirus‐2” (SARS‐CoV‐2) by the World Health Organization. 2 , 3 COVID‐19 is associated with several clinical signs among patients, mostly such as fever, cough, and fatigue, followed by rare cases of congestion, rhinorrhea, sore throat, and diarrhea. 4 , 5 , 6 Those 2019‐nCoV infection clinical features common with the SARS‐COV‐1 and Middle East Respiratory Syndrome (MERS) have included fever, dry cough, dyspnea, and bilateral ground‐glass opacities by chest computerized tomography (CT) scans. Moreover, COVID‐19 causes immune dysfunction, acute respiratory distress syndrome (ARDS) as well as multiorgan failure. Among patients suffering from severe COVID‐19, ARDS is the most common and destructive form of the disease. 6 , 7 ARDS is developed by a series of mechanisms including the abnormal activity of the renin‐angiotensin apparatus, cytokine storm, neutrophil stimulation, vitamin D receptor (vdr) gene expression, oxidative stress, and enhanced coagulopathies. 8 , 9 , 10 , 11 The most frequently reported laboratory abnormalities included increased levels of C‐reactive protein (CRP) and lactate dehydrogenase (LDH) and reduced lymphocyte count. 12 Cytokine storm and various genetic variations/polymorphisms in the host defense system predispose to a severe SARS‐COV‐2 disease via affecting the level of the encoded protein. 13 , 14 Genetic variations in the host body such as immune‐related genes and also the SARS‐COV‐2 variants determine the clinical outcome of the disease. Therefore, in this study, those genetic variations mostly of encoding genes associated with the immune responses to the COVID‐19 disease predisposition or individual vulnerability were reviewed during 2019‐2022.

2. SARS‐COV‐2 PATHOPHYSIOLOGY AND RISK FACTORS

Following the binding (via viral spike/S, small envelope glycoprotein/E, and membrane/M) and penetration of the SARS‐COV‐2 into the respiratory epithelial cells via binding to the angiotensin‐converting enzyme‐2 (ACE2) receptors mostly by viral spike protein, some proinflammatory cytokines are secreted 15 , 16 (Figures 1 and 2). These cytokines include interferons, granulocyte colony‐stimulating factor (G‐CSF, filgrastim), monocyte chemoattractant protein 1 (MCP‐1), interleukin 1 B (IL1B), endothelial growth factor (EGF), IL6, IFNγ, IP10, macrophage inflammatory protein A (MIP‐1α or MIP1A), tumor necrosis factor (TNF)‐α, IL8, IL4, and IL10, and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc.). 17 , 18 , 19 Higher levels of IL2, IL6, IL7, IL10, IP10, MCP‐1, IL17A, TNF‐α, MIP1A, and GCSF have been determined among those patients with severe SARS‐COV‐2 or cytokine storm and also T cell lymphopenia compared to those with mild or moderate infection. 20 , 21 High IL6 serum levels have been associated with some conditions such as pneumonia (early death, plus TNF‐α), asthma, atopic dermatitis, and COVID‐19 severity. Noticeably, polymorphisms in cytokines result in their serum variations which alter (positive or negative) proinflammatory responses to SARS‐COV‐2.

Figure 1.

Figure 1

Open in a new tab

Mechanisms of SARS‐COV‐2 binding to the ACE2 receptor and cell penetration. ACE2, angiotensin‐converting enzyme‐2; SARS‐COV‐2, severe acute respiratory syndrome coronavirus‐2; TMPRSS2, transmembrane protease serine‐type 2.

Figure 2.

Figure 2

Open in a new tab

The mechanism of cytokine storm induction in SARS‐COV‐2 pathophysiology. SARS‐COV‐2, severe acute respiratory syndrome coronavirus‐2.

Male gender, older ages (>65 years), underlying medical conditions (diabetes, cancer, hypertension, chronic respiratory, and cardiovascular disorders), and chronic obstructive pulmonary disease (COPD) include major risk factors. Other significant factors include overweight, tobacco exposure, high LDH and International normalized ratio, low SPO2, serum albumin, public education/community knowledge and behaviors, antiviral use policies, individual/familial/population genetics, racial factors (non‐Hispanic Blacks), and lymphopenia <900/mm3. 22 , 23 , 24 , 25 , 26 , 27 The gender differences in responses to SARS‐COV‐2 attribute to the important role of X‐linked genes participating in immune stimulation. Lower socioeconomic conditions have also played a significant role in the COVID‐19 vulnerability. 28

3. HUMAN GENETIC VARIATIONS AND COVID‐19 SEVERITY

Human genetic variations have been demonstrated to associate with COVID‐19 severity. Genome wide association studies have demonstrated major genetic mutations including SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1, 29 , 30 ABO (rs657152, rs9411378, and rs912805253), INFAR2 (rs2236757 and rs13050728), Oligoadenylate synthetases (OAS1 and OAS3), dipeptidyl peptidase 4 (DPP4/CD26) rs13015258, 29 , 30 DPP9, intercellular adhesin molecules (ICAM5), tyrosine kinase 2 (TYK2), human leukocyte antigens (HLA‐G, HLA‐DPB1), coiled‐coil α‐helical rod protein 1 (CCHCR1), ACE2, Mucin 5B (MUC5B), and Forkhead box P4 (FOXP4). 29 , 30 , 31 , 32 , 33 , 34 Moreover, this association has been deciphered regarding single nucleotide polymorphisms (SNPs) in the interferons, IL1, TNF, toll‐like receptors (TLRs), IL6, IL10, IL17 genes, and those encoding transmembrane protease serine‐type 2 (TMPRSS2), glucose‐regulated protein 78 kDa (GRP78), ERAP2, Adam17, APOE, and PCSK3, cluster of differentiation 147 (CD147), 2′‐5′‐Oligoadenylate synthases (Oas) (p.Arg47Gln, p.Ile99Val, and p.Arg130His), HLA‐B*46:01/A25:01/C01:02, CCR9, CXCR6, SLC6A20, and CRP (rs1205) which predispose SARS‐COV‐2 infection. 35 , 36 , 37 , 38 , 39 , 40 Similar relations were unraveled regarding variations in genes encoding UNC13D and AP3B1 germline associated proteins to the SARS‐COV‐2 infection. 41 The post‐COVID‐19 pulmonary fibrosis has also been associated with some genetic mutations such as in MUC5B and TERT genes. Genetic mutations in chromosomes 5q32 and 12q22 loci have been associated with COVID‐19 severity. 42 SNPs have caused serum variations in related encoded proteins which substantially alter immune responses in exposure to SARS‐COV‐2 and dictate the outcome of the disease. In addition, it was recently unraveled that the SERPINE1 rs6092 variant was associated with impaired coagulation among SARS‐COV‐2 infected patients. 43

4. INTERFERONS POLYMORPHISMS

Interferons responses impairments diminish the antiviral capacity. An SNP within the interferon‐induced transmembrane protein 3 (IFITM3) gene (rs12252‐C/C) has been associated with influenza and COVID‐19 severity. 44 , 45 , 46 , 47 This variant has been also associated with intensive care unit (ICU) admission. IFNAR1 (p.Trp73Cys, p.Ser422Arg, and p.Pro335del) and IFNAR2 (p.Glu140fs) and rs2236757—A/G variants have been associated with increased levels of SARS‐COV‐2. The IFN‐β (rs2071430—G/T) and INF‐γ SNPs in African and Asian populations have been related to the infection of both SARS COV and COVID‐19. 30 , 48 Moreover, IFN‐γ + 874A/T (rs2430561) and A/C polymorphisms were associated with severe SARS COV in Chinese population. 49 Additionally, some loss of function variants of interferons (TBK1, IFIH1, IRF3, IRF7, and also TLR3) have been associated with severe disease. 48 , 50

5. TNF GENE POLYMORPHISMS

TNF‐α has an important role in the acute phase of inflammation and chronic degenerative diseases. 51 TNF‐α levels increase during respiratory viral infections and the encoding gene SNPs association with SARS COV was shown by Wang et al. 52 However, TNF rs1800629, causing TNF‐α serum level enhancement and higher reaction to inflammation, has played a protective role against pediatrics sepsis, while TNF‐863C/A (rs1800630) has increased the risk. Therefore, these mutations are age‐dependent. Furthermore, the TNF rs909253 allele has been significantly more common in COVID‐19 patients than in the control population. 53 In a recent study, TNFRSF1B rs3397 or TT genotype was associated with lower Horowitz index (PaO2/FiO2 ratio) compared to CT + CC genotypes being related to different TNFR1 and TNFR2 levels. 54

6. INTERLEUKINS POLYMORPHISMS

IL1 RN (rs315952—T/C) and IL4 (rs2070874—C/T/IL4 + 1059 C/T) SNPs have been associated with COVID‐19 severity. 55 , 56 The SNPs in the IL6 gene have been associated with pneumonia and COPD and also certain viral infections such as hepatitis B virus, hepatitis C virus (HCV), and influenza virus. 57 , 58 , 59 Low rate of IL6 CC (rs1800795) SNP was related to the persistence of HCV infection. 57 A study revealed that IL6 rs1800795 G allele protected against pneumonia‐induced sepsis, but IL10 rs1800896 A allele enhanced the risk of the disease. 60 Moreover, 7p15.3 (IL6–174C allele) has been related to the severity of pneumonia and COVID‐19. IL6 also affects the CD4+ T cells' fate and causes the COVID‐19 severity. 61 , 62 , 63 In addition, IL6, IL10, and IL12B SNPs have been associated with daily death rates mainly due to hypertension, cardiovascular diseases, obesity, and asthma. 64 , 65 , 66 , 67 In a study, among severely ill COVID‐19 patients (n = 100), the IL6 gene was significantly expressed higher compared to that in the control population (n = 324) which was correlated to the higher mortality rate. They determined that IL6 rs1800795 and rs2228145 SNPs were associated with severe forms of the COVID‐19. 68 Moreover, IL6 rs1800797 and rs1800795 SNPs have been related to alterations in serum levels and exacerbation of various diseases. 69 , 70 , 71

Furthermore, IL10 rs1518110 SNP has been related to its overexpression and disease severity. 72 However, in some studies, the IL10 SNPs have not been associated with the SARS COV. 49 , 73 , 74 , 75 In addition, the significant association of IL‐17A AG (rs2275913), IL17F TT (rs763780), and IL10 AG (rs1800896) SNPs with international severity and death outcome due to the COVID‐19 has been deciphered. 73 Noticeably, IL10 rs1800871 and rs1800872 genotypes among 193 COVID‐19 patients, were not significantly associated with the disease severity 76 (Table 1). IL17 gene polymorphisms have been associated with ARDS, SARS COV, MERS, and SARS‐COV‐2 in which the decrease in the IL17 levels was protective, but increased levels were related to the disease severity. It has been exhibited that enhanced circulating and alveolar levels of IL17A have been associated with neutrophil recruitment, alveolar permeability, and organ dysfunction in ARDS. 77 A hypothetic paper proposed the role of IL17 in the stimulation of proinflammatory responses and cytokine storm in COVID‐19 and also proposed to target IL17 as a therapeutic route for improving the symptoms. 78

Table 1.

Major genetic variations (SNPs) in the immune‐related genes, mainly of cytokines associated with the susceptibility to the COVID‐19.

Gene Genotype Effects
TMPRSS2 rs2070788, rs9974589, rs7364083 SARS‐COV‐2 infection
TNF promoter rs1800630 Higher reaction to inflammation
IL1A rs1946518 COVID‐19 severity
IL10 rs1800872, rs1800896, rs8178562 Overexpression, enhanced death outcome
IL6 rs1800795, rs2228145 Increased serum level, disease severity
IL17A rs2275913 International severity and death outcome
IL17F rs763780
IFN‐β rs2071430 SARS and COVID‐19 severity
IFNAR2 rs2236757 COVID‐19 severity
CXCR2 rs1126579 COVID‐19 severity
TNFRSF1B rs1061624, rs3397 COVID‐19 severity
IFITM3 rs12252 SARS‐COV‐2 severity
CD26/DPP4 rs13015258 SARS‐COV‐2 infection
DBP rs7041 COVID‐19 prevalence and mortality
TLR3 rs3775290 SARS‐COV‐2 infection
TLR7 rs179008 Low expression, SARS‐COV‐2 infection
TLR4 rs4986790, rs4986791 Higher serum levels of IL6, SARS‐COV‐2 infection
Open in a new tab

Abbreviations: CXCR2, CXC chemokine receptor‐2; IFITM3, interferon‐induced transmembrane protein 3; SARS‐COV‐2, severe acute respiratory syndrome coronavirus‐2; SNPs, single nucleotide polymorphisms; TLR, toll‐like receptor; TMPRSS2, transmembrane protease serine‐type 2; TNFRSF1B, tumor necrosis factor receptor 2.

7. CHEMOKINES POLYMORPHISMS

Chromosome 3 (3p21) loci variations have been suggested to play a role in COVID‐19 severity. 29 Some putative coreceptors genes (LZTFL1, SCL6A20, and FYCO1) and chemokines and their receptors have been mentioned such as XCR1, CCR6, and CCR9. Moreover, flanking genes (CCR1, CCR2, and CCR3) are also considerable. 79 It has been unraveled that CXCR6 and CCR9 chemokine receptor genes play an important role in the COVID‐19 protection in lung and whole blood, respectively. 80

8. CYTOKINES RECEPTORS POLYMORPHISMS

It was primarily found that various cytokines and VEGF have higher serum levels in COVID‐19 patients compared to healthy subjects, suggesting that cytokines and their receptors play a role in the disease development. 81 , 82 , 83 A bioinformatics anticipation study using cloud‐based software tools demonstrated that VEGF Q472H (rs1870377) CXCR2 rs1126579, TNFRSF1B rs1061624, and IL10RB rs8178562 receptors SNPs were possibly related to severe COVID‐19. The three latter SNPs cleave the mRNAs−miRNA binding sites. 83

9. TLRs GENES POLYMORPHISMS

TLRs recognize pathogen‐associated molecular patterns and response to pathogens through elicit of acquired immunity such as proinflammatory cytokines release (TNF‐α, IL1 β, and IL6 by TLR3 and IFN‐α, IFN‐β, and IFN‐λ by TLR7). 84 , 85 TLR3 gene expression has regulated the influenza A virus and rhinovirus infection. 86 , 87 , 88 TLR3 rs3775290 heterozygous genotype “C/T” has been associated with the HCV infection. 89 Additionally, the TLR7 rs179008 genotype has exacerbated bronchial asthma. 90 More relevantly, the elimination of SARS‐COV‐2 has been facilitated by TLRs2‐9 (mostly TLRs 3 and 7) pool. 91 , 92 , 93 Mice deficient in some TLRs encoding genes such as TLR3, and allelic variation (Ticam2) and TLR7 have exhibited higher SARS‐COV‐2 infection. The intron variant in the IFNAR2 gene (rs2236757) and Interferon‐inducible transmembrane (IFITM) genes such as IFITM3 rs12252 genotype has been associated with SARS‐COV‐2 infection. 94 It was demonstrated that the TLR3 rs3775290 and TLR7 rs179008 genotypes were significantly associated with increased risk of COVID‐19 pneumonia but not the disease outcome. 95 They also found that males with TLR3 SNP (T/T polymorphism) were more susceptible to the disease. TLR7 rs179008 genotype has been also associated with lower expression levels and additionally, HCV and HIV infection with alteration in responses. Another study in Egypt, demonstrated that among 300 adult patients with COVID‐19, TLR4 gene (Asp299Gly or rs4986790, and Thr399Ile or rs4986791) SNPs were significantly higher among patients correlating with higher serum levels of IL6. 96 A study among 150 middle‐aged COVID‐19 patients and 135 healthy volunteers exhibited that TLR7 (rs3853839) GG genotype was significantly more frequent in COVID‐19 patients compared to control population (38.7% vs. 4.4%). Additionally, TLR7 mRNA expression levels were significantly higher among patients, particularly among those with GG genotype (rs3853839). Moreover, significantly lower WBC but higher IL6, CRP, and ferritin levels were observed among patients. 97 Therefore, these SNPs were correlated with SARS‐COV‐2 infection, cytokine storm, and patients' higher mortality rates. In addition, TLR9 rs352162, rs352162, and rs187084 SNPs were associated with HCV infection and ICU admission. It was hypothesized that TLR‐9 may also participate in the combat against COVID‐19. Owing to the high rate of CpG‐Motifs in the SARS viral sequence, TLR9 controversially participates in lung complications. 98 Hence, the use of TLR9 antagonists in combination with the Remdesivir possibly contributes to COVID‐19 disease improvement.

10. SARS‐COV‐2 VARIANTS AND IMMUNE ESCAPE

Our aim in this section was to uncover the association of host genetics and SARS‐COV‐2 variants such as VOCs, however, to the best of our knowledge, there is no published data in this regard. There has been cross‐reactivity between various vaccines and COVID‐19 variants related to immune responses. 99 , 100 , 101 These data points supposedly elicit similar immune responses by genotype variants of COVID‐19. Delta variant (60% more transmissible than alpha variant) has shown resistance to some monoclonal antibodies such as bamlanivimab. Additionally, sera from convalescent individuals were fourfold less reactive against the Delta variant. 102 , 103 However, this study did not provide any evidence of host immune gene mutations. A variation in the receptor‐binding β‐loop‐β motif of Delta variant (B.1.617.2) spike protein was associated with lower avidity to neutralizing antibodies. 104 Furthermore, mutations in the Omicron variant such as spike protein have an outstanding effect on the immune escape. 105 Novel mutations in the SARS‐COV‐2 genome have been depicted in Table 2. 106 , 107 , 108 Hence, particular relation between host immune gene variations and the infection of SARS‐COV‐2 VOCs is warranted in future studies.

Table 2.

Novel mutations in the SARS‐COV‐2 genome.

Gene Motif variation SARS‐COV‐2 variant
ORF1a ∆106‐108, L438P, T85I B.1.526
T100I, A1708D, 12230T, ∆3675‐3677 B.1.1.7
T265I, K1655N, K3533R, ∆3675‐3677 B.1.351
S1188C, A1795Q, ∆3675‐3677 P.1
ORF1b Q88H, P323L B.1.526
P314L B.1.1.7
P314L B.1.351
P314L P.1
P323L B.1.36
D1183Y B.1.427/429
E1264D P.1
Accessory protein 3a Q57H B.1.526
Q57H B.1.351
S253P P.1
Accessory protein 8 Q27, R52I, Y73C B.1.1.7
E92K P.1
Nucleocapsid protein D3L, G204R, S235F, T205I B.1.1.7
R203K, G204R, P80R P.1
A12G B.1.525
P199L, M234I B.1.526
Envelope protein L21F B.1.525
P71L B.1.351
Membrane protein C64F B.1.525
I82T B.1.36
Spike protein

L18F, T20N, P26S, ∆69‐70, D138Y, ∆144, R190S, ∆242‐244, K417N/T, N440K, E484K/Q, N501Y, D614G/R, H655Y, T1027I, V1176F

L5F, T95I, D253G, D614G/R, A701V

S13I. R21T, W152C, E154Q, Q218H, E484K/Q, L452R, D614G/R, P681R

H1101Q, P681R

Q52R, A67V, Y453F, D614G/R, Q677H, F888L

B80A, D215G, R246I, K417N/T, F484K/Q, N501Y, D614G/R

M1229I, I692V, Y453F

P.1

B.1.526

B.1.427/429

B.1.617

B.1.525

B.1.351

B.1.298
Open in a new tab

Abbreviation: SARS‐COV‐2, severe acute respiratory syndrome coronavirus‐2.

11. CONCLUSION

Host genetic variations in particular those related to the immune responses determine the patients' susceptibility and COVID‐19 disease and related pathophysiology. Immune gene polymorphisms such as in interferons, IL1, IL4, IL6, IL7, IL10, and IL17 genes predispose patients to develop severe COVID‐19. Various cytokine and chemokine polymorphisms and receptors are associated with the outcome of COVID‐19 depending on the effect of occurring variation. TNF gene SNPs has been associated with higher/intense inflammatory responses. Genetic variations in TLR3, TLR4, TLR7, and TLR9 genes have been related to the COVID‐19 severe respiratory symptoms. However, the specific association of SARS‐COV‐2 VOCs and host genetic mutations in the disease severity remains to be uncovered. Prescription of cytokine storm inhibitors such as corticosteroids, cyclosporine, and etoposide to regulate the T cells responses can be helpful.

AUTHOR CONTRIBUTIONS

Mohammad Kazem Vakil, Yaser Mansoori, Ghaidaa Raheem Lateef Al‐Awsi, Ali Hosseinipour, Samaneh Ahsant, Sedigheh Ahmadi, Mohammad Ekrahi, Zahra Montaseri, Babak Pezeshki, Poopak Mohaghegh, Mojtaba Sohrabpour, Alireza Tavassoli, Abdolmajid Ghasemian, and Maryam Bahmanyar have conceptualized, read, prepared, and modified the final draft of the manuscript for submission. Abdolreza Daraei and Tahereh Dadkhah Jouybari has contributed in conceptualization and data collection. All the authors have read and finalized the submitted version of the manuscript.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Vakil MK, Mansoori Y, Al‐Awsi GRL, et al. Individual genetic variability mainly of proinflammatory cytokines, cytokine receptors and toll‐like receptors dictates pathophysiology of COVID‐19 disease. J Med Virol. 2022;94:4088‐4096. 10.1002/jmv.27849

Mohammad Kazem Vakil and Yaser Mansoori are co‐first authors.

Contributor Information

Alireza Tavassoli, Email: tavassoli.a@gmail.com.

Abdolmajid Ghasemian, Email: majidghasemian86@gmail.com.

DATA AVAILABILITY STATEMENT

Data are available from the corresponding author upon reasonable request.

REFERENCES

  • 1. World Health Organization . Situation report 1: novel coronavirus (2019‐nCoV). Vol 76. 2020;71‐76. [Google Scholar]
  • 2. World Health Organization . Coronavirus disease (COVID‐19). World Health Organization; 2021. [Google Scholar]
  • 3. hochak N, Singhal T, Kabra S, Lodha R. Pathophysiology of COVID‐19: why children fare better than adults? Indian J Pediatr. 2020;87(7):537‐546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Wu D, Wu T, Liu Q, Yang Z. The SARS‐CoV‐2 outbreak: what we know. Int J Infect Dis. 2020;94:44‐48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Wang W, Xu Y, Gao R, et al. Detection of SARS‐CoV‐2 in different types of clinical specimens. JAMA. 2020;323(18):1843‐1844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Poletti P, Tirani M, Cereda D, et al. Association of age with likelihood of developing symptoms and critical disease among close contacts exposed to patients with confirmed SARS‐CoV‐2 infection in Italy. JAMA Netw Open. 2021;4(3):e211085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Sheervalilou R, Shirvaliloo M, Dadashzadeh N, et al. COVID‐19 under spotlight: a close look at the origin, transmission, diagnosis, and treatment of the 2019‐nCoV disease. J Cell Physiol. 2020;235(12):8873‐8924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Hirano T, Murakami M. COVID‐19: a new virus, but a familiar receptor and cytokine release syndrome. Immunity. 2020;52(5):731‐733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Badellino H, Gobbo ME, Torres E, Aschieri ME. Early indicators and risk factors associated with mental health problems during COVID‐19 quarantine: is there a relationship with the number of confirmed cases and deaths? Int J Soc Psychiatry. 2021;67(5):567‐575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Anastassopoulou C, Gkizarioti Z, Patrinos GP, Tsakris A. Human genetic factors associated with susceptibility to SARS‐CoV‐2 infection and COVID‐19 disease severity. Hum Genomics. 2020;14(1):1‐8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Rokni M, Ahmadikia K, Asghari S, Mashaei S, Hassanali F. Comparison of clinical, para‐clinical and laboratory findings in survived and deceased patients with COVID‐19: diagnostic role of inflammatory indications in determining the severity of illness. BMC Infect Dis. 2020;20(1):1‐11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Hu B, Huang S, Yin L. The cytokine storm and COVID‐19. J Med Virol. 2021;93(1):250‐256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Sarzi‐Puttini P, Giorgi V, Sirotti S, et al. COVID‐19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol. 2020;38(2):337‐342. [PubMed] [Google Scholar]
  • 14. Solé‐Violán J, de Castro Fv, García‐Laorden MI, et al. Genetic variability in the severity and outcome of community‐acquired pneumonia. Respir Med. 2010;104(3):440‐447. [DOI] [PubMed] [Google Scholar]
  • 15. Hamming I, Timens W, Bulthuis M, Lely A, Navis Gvvan Goor, H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631‐637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Tan M, Liu Y, Zhou R, et al. Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China. Immunology. 2020;160(3):261‐268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Kim JS, Lee JY, Yang JW, et al. Immunopathogenesis and treatment of cytokine storm in COVID‐19. Theranostics. 2021;11(1):316‐329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39(5):529‐539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Vanderbeke L, Van Mol P, Van Herck Y, et al. Monocyte‐driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID‐19 disease severity. Nat Commun. 2021;12(1):1‐15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Gaitzsch E, Passerini V, Khatamzas E, et al. COVID‐19 in patients receiving CD20‐depleting immunochemotherapy for B‐cell lymphoma. Hemasphere. 2021;5(7):603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Bonuomo V, Ferrarini I, Dell'Eva M, Sbisà E, Krampera M, Visco C. COVID‐19 (SARS‐CoV‐2 infection) in lymphoma patients: a review. World J Virol. 2021;10(6):312‐325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Phillips N, Park I‐W, Robinson JR, Jones HP. The perfect storm: COVID‐19 health disparities in US Blacks. J Racial Ethn Health Disparities. 2021;8(5):1153‐1160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Zhou Y, Chi J, Lv W, Wang Y. Obesity and diabetes as high‐risk factors for severe coronavirus disease 2019 (Covid‐19). Diabetes Metab Res Rev. 2021;37(2):e3377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Chen R, Liang W, Jiang M, et al. Risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in China. Chest. 2020;158(1):97‐105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Chou R, Dana T, Buckley DI, Selph S, Fu R, Totten AM. Epidemiology of and risk factors for coronavirus infection in health care workers: a living rapid review. Ann Intern Med. 2020;173(2):120‐136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Tsabouri S, Makis A, Kosmeri C, Siomou E. Risk factors for severity in children with coronavirus disease 2019: a comprehensive literature review. Pediatr Clin. 2021;68(1):321‐338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Shi SM, Bakaev I, Chen H, Travison TG, Berry SD. Risk factors, presentation, and course of coronavirus disease 2019 in a large, academic long‐term care facility. J Am Med Dir Assoc. 2020;21(10):1378‐1383 .e1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Bermudi PMM, Lorenz C, de Aguiar BS, Failla MA, Barrozo LV, Chiaravalloti‐Neto F. Spatiotemporal ecological study of COVID‐19 mortality in the city of São Paulo, Brazil: shifting of the high mortality risk from areas with the best to those with the worst socio‐economic conditions. Travel Med Infect Dis. 2021;39:101945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Group SC‐G. Genomewide association study of severe Covid‐19 with respiratory failure. N Engl J Med. 2020;383(16):1522‐1534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Pairo‐Castineira E, Clohisey S, Klaric L, et al. Genetic mechanisms of critical illness in Covid‐19. Nature. 2021;591(7848):92‐98. [DOI] [PubMed] [Google Scholar]
  • 31. Shelton JF, Shastri AJ, Ye C, et al. Trans‐ancestry analysis reveals genetic and nongenetic associations with COVID‐19 susceptibility and severity. Nat Genet. 2021;53(6):801‐808. [DOI] [PubMed] [Google Scholar]
  • 32. Roberts GHL, Park DS, Coignet MV, et al. AncestryDNA COVID‐19 host genetic study identifies three novel loci. medRxiv. 2020;10(6):58‐64. [Google Scholar]
  • 33. Chakravarty S. COVID‐19: the effect of host genetic variations on host−virus interactions. J Proteome Res. 2020;20(1):139‐153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Velavan TP, Pallerla SR, Rüter J, et al. Host genetic factors determining COVID‐19 susceptibility and severity. EBioMedicine. 2021;72:103629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Mohammadpour S, Torshizi Esfahani A, Halaji M, Lak M, Ranjbar R. An updated review of the association of host genetic factors with susceptibility and resistance to COVID‐19. J Cell Physiol. 2021;236(1):49‐54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Thierry AR. Host/genetic factors associated with COVID‐19 call for precision medicine. Precis Clin Med. 2020;3(3):228‐234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Debnath M, Banerjee M, Berk M. Genetic gateways to COVID‐19 infection: implications for risk, severity, and outcomes. FASEB J. 2020;34(7):8787‐8795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. von der Thüsen J, van der Eerden M. Histopathology and genetic susceptibility in COVID‐19 pneumonia. Eur J Clin Invest. 2020;50(7):e13259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. 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):1‐8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Guilger‐Casagrande M, De Barros CT, Antunes VA, De Araujo DR, Lima R. Perspectives and challenges in the fight against COVID‐19: the role of genetic variability. Front Cell Infect Microbiol. 2021;11:150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Luo H, Liu D, Liu W, et al. Germline variants in UNC13D and AP3B1 are enriched in COVID‐19 patients experiencing severe cytokine storms. Eur J Human Genet. 2021;29(8):1312‐1315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Chamnanphon M, Pongpanich M, Suttichet TB, et al. Host genetic factors of COVID‐19 susceptibility and disease severity in a Thai population. J Hum Genet. 2022;67:1‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Fricke‐Galindo I, Buendia‐Roldan I, Chavez‐Galan L, et al. SERPINE1 rs6092 variant is related to plasma coagulation proteins in patients with severe COVID‐19 from a Tertiary Care Hospital. Biology. 2022;11(4):595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Chen T, Xiao M, Yang J, et al Association between rs12252 and influenza susceptibility and severity: an updated meta‐analysis. Epidemiol Infect. 2019:​ 147. 10.1017/S0950268818002832 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Zhang Y‐H, Zhao Y, Li N, et al. Interferon‐induced transmembrane protein‐3 genetic variant rs12252‐C is associated with severe influenza in Chinese individuals. Nat Commun. 2013;4(1):1‐6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Gómez J, Albaiceta GM, Cuesta‐Llavona E, et al. The interferon‐induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID‐19. Cytokine. 2021;137:155354. [DOI] [PubMed] [Google Scholar]
  • 47. Duncan CJ, Mohamad SM, Young DF, et al. Human IFNAR2 deficiency: lessons for antiviral immunity. Sci Transl Med. 2015;7(307):307ra154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life‐threatening COVID‐19. Science. 2020;370(6515):eabd4570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Chong WP, Ip WE, Tso GHW, et al. The interferon gamma gene polymorphism+ 874 A/T is associated with severe acute respiratory syndrome. BMC Infect Dis. 2006;6(1):1‐4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Asgari S, Schlapbach LJ, Anchisi S, et al. Severe viral respiratory infections in children with IFIH1 loss‐of‐function mutations. Proc Natl Acad Sci. 2017;114(31):8342‐8347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Silva LB, Sampaio GM, Cunha RSC, et al. The genetic polymorphism of TNF‐α associated with the anti‐TNF‐α therapy used for COVID‐19 patients—another possible approach. Res Soc Dev. 2022;11(1):e47411121576. [Google Scholar]
  • 52. Wang S, Wei M, Han Y, et al. Roles of TNF‐α gene polymorphisms in the occurrence and progress of SARS‐Cov infection: a case‐control study. BMC Infect Dis. 2008;8(1):1‐10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Heidari Nia M, Rokni M, Mirinejad S, et al. Association of polymorphisms in tumor necrosis factors with SARS‐CoV‐2 infection and mortality rate: a case‐control study and in silico analyses. J Med Virol. 2022;94(4):1502‐1512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Fricke‐Galindo I, Buendía‐Roldán I, Ruiz A, et al. TNFRSF1B and TNF variants are associated with differences in soluble TNF receptors' levels in patients with severe COVID‐19. J Infect Dis;. 2022;​ jiac 101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Meyer NJ, Ferguson JF, Feng R, et al. A functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock. Am J Respir Crit Care Med. 2014;190(6):656‐664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Paim AAO, Lopes‐Ribeiro Á, Daian E Silva DSO, et al. Will a little change do you good? A putative role of polymorphisms in COVID‐19. Immunol Lett. 2021;235:9‐14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Murphy EA, Davis JM, Brown AS, Carmichael MD, Ghaffar A, Mayer EP. Effect of IL‐6 deficiency on susceptibility to HSV‐1 respiratory infection and intrinsic macrophage antiviral resistance. J Interferon Cytokine Res. 2008;28(10):589‐596. [DOI] [PubMed] [Google Scholar]
  • 58. Fang Z, Li J, Yu X, et al. Polarization of monocytic myeloid‐derived suppressor cells by hepatitis B surface antigen is mediated via ERK/IL‐6/STAT3 signaling feedback and restrains the activation of T cells in chronic hepatitis B virus infection. J Immunol. 2015;195(10):4873‐4883. [DOI] [PubMed] [Google Scholar]
  • 59. Malchow S, Thaiss W, Jänner N, et al. Essential role of neutrophil mobilization in concanavalin A‐induced hepatitis is based on classic IL‐6 signaling but not on IL‐6 trans‐signaling. Biochim Biophys Acta. 2011;1812(3):290‐301. [DOI] [PubMed] [Google Scholar]
  • 60. AL‐Eitan LN, Alahmad SZ. Pharmacogenomics of genetic polymorphism within the genes responsible for SARS‐CoV‐2 susceptibility and the drug‐metabolising genes used in treatment. Rev Med Virol. 2021;31(4):e2194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Linnik JE, Egli A. Impact of host genetic polymorphisms on vaccine induced antibody response. Hum Vaccines Immunother. 2016;12(4):907‐915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Riazalhosseini B, Mohamed Z, Apalasamy YD, Shafie NS, Mohamed R. Interleukin‐6 gene variants are associated with reduced risk of chronicity in hepatitis B virus infection in a Malaysian population. Biomed Rep. 2018;9(3):213‐220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Lange A, Lange J, Jaskuła E. Cytokine overproduction and immune system dysregulation in alloHSCT and COVID‐19 patients. Front Immunol. 2021;12:2068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Tang F, Liu W, Zhang F, et al. IL‐12 RB1 genetic variants contribute to human susceptibility to severe acute respiratory syndrome infection among Chinese. PLoS One. 2008;3(5):e2183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Padrón‐Morales J, Sanz C, Dávila I, Muñoz‐Bellido F, Lorente F, Isidoro‐Garcia M. Polymorphisms of the IL12B, IL1B, and TNFA genes and susceptibility to asthma. J Investig Allergol Clin Immunol. 2013;23(7):487‐494. [PubMed] [Google Scholar]
  • 66. Timasheva Y, Nasibullin T, Zakirova A, Mustafina O. Association of interleukin‐6, interleukin‐12, and interleukin‐10 gene polymorphisms with essential hypertension in Tatars from Russia. Biochem Genet. 2008;46(1):64‐74. [DOI] [PubMed] [Google Scholar]
  • 67. Yılmaz V, Yentür SP, Saruhan‐Direskeneli G. IL‐12 and IL‐10 polymorphisms and their effects on cytokine production. Cytokine. 2005;30(4):188‐194. [DOI] [PubMed] [Google Scholar]
  • 68. Smieszek SP, Przychodzen BP, Polymeropoulos VM, Polymeropoulos CM, Polymeropoulos MH. Assessing the potential correlation of polymorphisms in the IL6R with relative IL6 elevation in severely ill COVID‐19 patients'. Cytokine. 2021;148:155662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Tong Y, Wang Z, Geng Y, et al. The association of functional polymorphisms of IL‐6 gene promoter with ischemic stroke: analysis in two Chinese populations. Biochem Biophys Res Commun. 2010;391(1):481‐485. [DOI] [PubMed] [Google Scholar]
  • 70. González‐Castro TB, Hernández‐Díaz Y, Pérez‐Hernández N, et al Interleukin 6 (rs1800795) gene polymorphism is associated with cardiovascular diseases: a meta‐analysis of 74 studies with 86,229 subjects. EXCLI J. 2019;18:331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Dar SA, Haque S, Mandal RK, et al. Interleukin‐6‐174G> C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: a case‐control study and meta‐analysis. Autoimmunity. 2017;50(3):158‐169. [DOI] [PubMed] [Google Scholar]
  • 72. Chou S‐C, Ko H‐W, Lin Y‐C. CRP/IL‐6/IL‐10 single‐nucleotide polymorphisms correlate with the susceptibility and severity of community‐acquired pneumonia. Genet Test Mol Biomarkers. 2016;20(12):732‐740. [DOI] [PubMed] [Google Scholar]
  • 73. Karcioglu Batur L, Hekim N. Correlation between interleukin gene polymorphisms and current prevalence and mortality rates due to novel coronavirus disease 2019 (COVID‐2019) in 23 countries. J Med Virol. 2021;93(10):5853‐5863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74. 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(10229):1054‐1062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Lau Y, Peiris J. Association of cytokine and chemokine gene polymorphisms. Hong Kong Med J. 2009;15(2):43‐46. [PubMed] [Google Scholar]
  • 76. Avendaño‐Félix M, Ochoa‐Ramírez LA, Ramos‐Payán R, et al. Lack of effects of the genetic polymorphisms of interleukin‐10 in clinical outcomes of COVID‐19. Viral Immunol. 2021;34(8):567‐572. [DOI] [PubMed] [Google Scholar]
  • 77. Pacha O, Sallman MA, Evans SE. COVID‐19: a case for inhibiting IL‐17? Nat Rev Immunol. 2020;20(6):345‐346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Maione F, Casillo GM, Raucci F, et al. Interleukin‐17A (IL‐17A): a silent amplifier of COVID‐19. Biomed Pharmacother. 2021;142:111980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79. Nakanishi T, Pigazzini S, Degenhardt F, et al. Age‐dependent impact of the major common genetic risk factor for COVID‐19 on severity and mortality. J Clin Invest. 2021;131(23):e152386. 10.1172/JCI152386 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Dai Y, Wang J, Jeong H‐H, Chen W, Jia P, Zhao Z. Association of CXCR6 with COVID‐19 severity: delineating the host genetic factors in transcriptomic regulation. Hum Genet. 2021;140(9):1313‐1328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497‐506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid‐19. N Engl J Med. 2020;383(2):120‐128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83. Karakas Celik S, Cakmak Genc G, Dursun A. A bioinformatic approach to investigating cytokine genes and their receptor variants in relation to COVID‐19 progression. Int J Immunogenet. 2021;48(2):211‐218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. Sadik NAH, Shaker OG, Ghanem HZ, Hassan HA, Abdel‐Hamid A‐HZ. Single‐nucleotide polymorphism of toll‐like receptor 4 and interleukin‐10 in response to interferon‐based therapy in Egyptian chronic hepatitis C patients. Arch Virol. 2015;160(9):2181‐2195. [DOI] [PubMed] [Google Scholar]
  • 85. Totura AL, Whitmore A, Agnihothram S, et al. Toll‐like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. mBio. 2015;6(3):e00638‐15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Hewson CA, Jardine A, Edwards MR, Laza‐Stanca V, Johnston SL. Toll‐like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. J Virol. 2005;79(19):12273‐12279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Silkoff PE, Flavin S, Gordon R, et al. Toll‐like receptor 3 blockade in rhinovirus‐induced experimental asthma exacerbations: a randomized controlled study. J Allergy Clin Immunol. 2018;141(4):1220‐1230. [DOI] [PubMed] [Google Scholar]
  • 88. Kimura G, Ueda K, Eto S, et al. Toll‐like receptor 3 stimulation causes corticosteroid‐refractory airway neutrophilia and hyperresponsiveness in mice. Chest. 2013;144(1):99‐105. [DOI] [PubMed] [Google Scholar]
  • 89. Mosaad YM, Metwally SS, Farag RE, Lotfy ZF, AbdelTwab HE. Association between toll‐like receptor 3 (TLR3) rs3775290, TLR7 rs179008, TLR9 rs352140 and chronic HCV. Immunol Invest. 2019;48(3):321‐332. [DOI] [PubMed] [Google Scholar]
  • 90. Møller‐Larsen S, Nyegaard M, Haagerup A, Vestbo J, Kruse TA, Børglum AD. Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders. Thorax. 2008;63(12):1064‐1069. [DOI] [PubMed] [Google Scholar]
  • 91. Khanmohammadi S, Rezaei N. Role of Toll‐like receptors in the pathogenesis of COVID‐19. J Med Virol. 2021;93(5):2735‐2739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92. Onofrio L, Caraglia M, Facchini G, Margherita V, Placido SD, Buonerba C. Toll‐like receptors and COVID‐19: a two‐faced story with an exciting ending. Future Sci. 2020;6:FSO605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. Manik M, Singh RK. Role of toll‐like receptors in modulation of cytokine storm signaling in SARS‐CoV‐2‐induced COVID‐19. J Med Virol. 2022;94(3):869‐877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Karaghiosoff M, Neubauer H, Lassnig C, et al. Partial impairment of cytokine responses in Tyk2‐deficient mice. Immunity. 2000;13(4):549‐560. [DOI] [PubMed] [Google Scholar]
  • 95. Alseoudy MM, Elgamal M, Abdelghany DA, et al. Prognostic impact of toll‐like receptors gene polymorphism on outcome of COVID‐19 pneumonia: a case‐control study. Clin Immunol. 2022;235:108929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Taha SI, Shata AK, Baioumy SA, et al. Toll‐like receptor 4 polymorphisms (896A/G and 1196C/T) as an indicator of COVID‐19 severity in a convenience sample of Egyptian patients. J Inflamm Res. 2021;14:6293‐6303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97. El‐Hefnawy SM, Eid HA, Mostafa RG, Soliman SS, Omar TA, Azmy RM. COVID‐19 susceptibility, severity, clinical outcome and Toll‐like receptor (7) mRNA expression driven by TLR7 gene polymorphism (rs3853839) in middle‐aged individuals without previous comorbidities. Gene Rep. 2022;27:101612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98. Bezemer GF, Garssen J. TLR9 and COVID‐19: a multidisciplinary theory of a multifaceted therapeutic target. Front Pharmacol. 2021;11:1958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99. Hammerschmidt SI, Bosnjak B, Bernhardt G, et al. Neutralization of the SARS‐CoV‐2 Delta variant after heterologous and homologous BNT162b2 or ChAdOx1 nCoV‐19 vaccination. Cell Mol Immunol. 2021;18(10):2455‐2456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100. Zhou R, Peng ToKKW, Chan Q, Huang JMC, Yang H. D, et al. Vaccine‐breakthrough infection by the SARS‐CoV‐2 omicron variant elicits broadly cross‐reactive immune responses. Clin Transl Med. 2022;12(1):720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101. Geng J, Chen L, Yuan Y, et al. CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS‐CoV‐2 and its variants delta, alpha, beta, and gamma. Signal Transduct Target Ther. 2021;6(1):1‐13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102. Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS‐CoV‐2 variant Delta to antibody neutralization. Nature. 2021;596(7871):276‐280. [DOI] [PubMed] [Google Scholar]
  • 103. Edara V‐V, Pinsky BA, Suthar MS, et al. Infection and vaccine‐induced neutralizing‐antibody responses to the SARS‐CoV‐2 B. 1.617 variants. N Engl J Med. 2021;385(7):664‐666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104. Baral P, Bhattarai N, Hossen ML, et al. Mutation‐induced changes in the receptor‐binding interface of the SARS‐CoV‐2 Delta variant B. 1.617. 2 and implications for immune evasion. Biochem Biophys Res Commun. 2021;574:14‐19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105. Hu J, Peng P, Cao X, et al. Increased immune escape of the new SARS‐CoV‐2 variant of concern Omicron. Cell Mol Immunol. 2022;19:1‐3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106. Dubey A, Choudhary S, Kumar P, Tomar S. Emerging SARS‐CoV‐2 variants: genetic variability and clinical implications. Curr Microbiol. 2022;79(1):1‐18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107. Lauring AS, Hodcroft EB. Genetic variants of SARS‐CoV‐2—what do they mean? JAMA. 2021;325(6):529‐531. [DOI] [PubMed] [Google Scholar]
  • 108. Akkiz H. Implications of the novel mutations in the SARS‐CoV‐2 genome for transmission, disease severity, and the vaccine development. Front Med. 2021;8:8. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data are available from the corresponding author upon reasonable request.

Articles from Journal of Medical Virology are provided here courtesy of Wiley

RESOURCES