• Users Online: 421
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 1  |  Page : 95-102

Genetic polymorphism of toll-like receptors in HIV-I infected patients with and without tuberculosis co-infection


1 Department of Medicine, All India Institute of Medical Sciences, New Delhi; University Institute of Applied Health Sciences, Chandigarh University, Mohali, Punjab, India
2 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
3 University Institute of Applied Health Sciences, Chandigarh University, Mohali, Punjab, India
4 Department of Microbiology, National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India

Date of Submission07-Jan-2022
Date of Decision22-Jan-2022
Date of Acceptance24-Feb-2022
Date of Web Publication12-Mar-2022

Correspondence Address:
Gaurav Kaushik
Department of Medicine, All India Institute of Medical Sciences, New Delhi, Professor at University Institute of Applied Health Sciences, Chandigarh University, Mohali, Punjab
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_4_22

Rights and Permissions
  Abstract 


Background: Toll-like receptors (TLRs) are identified as one of the key components of innate immune system due to their ability to sense conserved molecular motifs associated with several pathogens. It has been implicated from several evidence that mutations in genes encoding TLRs are associated with increased or decreased susceptibility to various infectious diseases. Methods: The study was prospective, cross-sectional, as well as longitudinal in nature, which includes 223 HIV-positive patients, 150 HIV-positive patients with latent tuberculosis (TB) infection, 150 HIV-positive patients with active TB, 200 HIV-negative newly diagnosed sputum smear positive pulmonary TB patients, and 205 healthy subjects. Results: A statistically significant difference was observed in allelic frequencies of TLR4 between healthy subjects and HIV + TB patients (P < 0.001), healthy subjects, and pulmonary TB (PTB) Category-I patients (P < 0.01) and between healthy subjects and HIV + TB patients (P < 0.001). TLR4 genotype frequencies were also significantly different between healthy subjects and PTB Cat I patients (P < 0.001) and HIV + and HIV + TB patients (P < 0.01). A statistically significant difference was also observed between HIV + and PTB Cat I patients (P = 0.04), HIV + LTBI and HIV + TB patients (P = 0.01), and between HIV + TB and PTB Cat I patients (P < 0.01). Conclusion: This study implicates that Asp299Gly polymorphism in TLR4 gene is associated with increased susceptibility to active TB in HIV-seropositive patients. Increased frequency of 'A' allele in TLR9 gene was also discovered at the time of active TB development in ART naïve HIV + patients, who developed active TB on follow-up.

Keywords: HIV, infectious diseases, toll-like receptors, tuberculosis


How to cite this article:
Kaushik G, Vashishtha R, Tripathi H, Yadav RN. Genetic polymorphism of toll-like receptors in HIV-I infected patients with and without tuberculosis co-infection. Int J Mycobacteriol 2022;11:95-102

How to cite this URL:
Kaushik G, Vashishtha R, Tripathi H, Yadav RN. Genetic polymorphism of toll-like receptors in HIV-I infected patients with and without tuberculosis co-infection. Int J Mycobacteriol [serial online] 2022 [cited 2022 May 25];11:95-102. Available from: https://www.ijmyco.org/text.asp?2022/11/1/95/339520




  Introduction Top


Globally, HIV resulted in 37.7 million (range, 30.2 million to 45.1 million) prevalent cases, 1.5 million (range, 1 million to 2 million) incident cases, and 680,000 deaths.[1] The seroprevalence of HIV reported in India is 0.22% (0.17%–0.29%), which corresponds to 23.48 lakhs people.[2]

Globally, TB control has been one of the major challenges to public health. It has been estimated that one-third of the world population, i.e., approximately 2 billion people of the world, are infected with TB bacilli. According to the World Health Organization,[3] there are estimated 5.8 million incident cases of TB globally.

In India, TB accounted for 2.64 million incident cases (of these, 71,000 cases occur among HIV-positive individuals) in 2019. Deaths arising due to TB were 26.9 lakhs in India.[4] It has been observed that out of the large number of people exposed to Mycobacterium tuberculosis, only 30% acquire TB infection and the remaining 70% remain uninfected. Of these 30% infected individuals, 10% develop active TB disease (i.e., primary disease), while in the remaining 90%, the infection is contained by the host defense system.[5] The presence of TB bacilli within the host in dormant or nonreplicating state is known as latent tuberculosis infection (LTBI).[6] Individuals with LTBI are asymptomatic, without any radiographic and bacteriological evidence of TB disease (American Thoracic Society. Diagnostic Standards and Classification of TB in adults and children 1999). However, resuscitation-promoting factors can reactivate the dormant bacteria.[7]

The host genetic factors which contribute to the risk of HIV infection include genetic variants that affect HIV entry (chemokine coreceptors and their ligands); acquired and innate immunity (major histocompatibility complex, Killer cell immunoglobulin like-receptors cytokines etc.); and intracellular replication and innate and adaptive immune responses of the host.[8],[9]

The human immune system is broadly classified into innate and adaptive immune systems. Innate immune system is evolutionary more ancient and acts as body's first line of defense against the foreign antigen.[10] Definite work on innate immune system leads to remarkable discovery of highly skillful phylogenetically conserved family of proteins known as pattern recognition receptors (PRRs). PRRs had ability to identify specific pathogen-associated molecular patterns (PAMPs).[11] The most potent of all PRRs which plays a central role in innate immune system is toll-like receptors (TLRs). Till date, 13 TLRs (TLR1-TLR13) were identified in mammalian species, and of these, 11 TLRs were found in humans.[12] TLRs are expressed on wide variety of cells (immune cells like macrophages, dendritic cells, B cells, and T cells and nonimmune cells like fibroblast and epithelial cell), tissues, and organs including lymphoid organs.[13] Some TLRs are expressed extracellularly on cell surface (TLRs 1, 2, 4, 5, and 6), while others (TLRs 3, 7, 8, and 9) intracellularly.[14] TLR10 gene is mostly expressed in lymphoid tissues such as spleen, lymph node, thymus, and tonsils. TLR11 is expressed in macrophages and dendritic cells. The exact function of TLR10 and TLR11 gene is still not known in humans.

Growing body of data has demonstrated that immune regulatory molecule such as human leukocyte antigen contributes to host-virus cross-talk. Genetic diversity or mutations are common in immune regulatory molecules and they contribute toward variation in susceptibility to infectious diseases (ID). The present study was planned to investigate the genetic variability in toll-like receptors (TLR2, TLR4, and TLR9) in HIV-I-infected patients with and without TB coinfection.


  Methods Top


Study setting and design

Patient consent form: Written informed consent was obtained from all the study participants before enrollment in the study.This study was carried out at the Department of Medicine, AIIMS, New Delhi, India. AIIMS is a tertiary care center with catchment area of several neighboring states.

Study population

The study population consisted of the following five groups: (i) HIV-positive patients without TB infection and disease (HIV + patients); (ii) HIV-positive patients with latent TB infection (HIV + LTBI patients); (iii) HIV-positive patients with active TB disease (HIV + TB patients); (iv) HIV-negative newly diagnosed sputum smear-positive pulmonary TB patients (PTB Cat I); and (v) healthy subjects.

Although the main study population was represented by the first three study groups, HIV-negative PTB Cat I patients were included as disease control and healthy subjects as healthy controls in the study.

All HIV-seropositive patients were recruited from the Infectious diseases Clinic, Medicine Department sponsored by the Ministry of Health and Family Welfare, Government of India, AIIMS, New Delhi.

HIV-negative, PTB Cat I patients were recruited from directly observed treatment short-course center, AIIMS, New Delhi, sponsored by the Ministry of Health and Family Welfare, Government of India.

Healthy subjects were recruited as controls from the community with the same socioeconomic status and ethnic background as that of the patients.

Exclusion criteria of the study

The following were the exclusion criteria of the study: (i) subjects with a history of TB; (ii) patients with multidrug-resistant TB (MDR-TB); (iii) pregnant and lactating females; (iv) study subjects with hepatitis B or C positivity; (v) presence of secondary immunodeficiency states among study subjects like organ transplantation, diabetes mellitus, malignancy, and treatment with corticosteroids (on detailed history and laboratory investigations); (vi) patients requiring surgical intervention; (vii) terminally ill patients as per treating clinician's judgment; and (viii) patients who had difficulty in follow-up.

Study procedure

The demographic and clinical information of all the recruited subjects was captured in the standardized questionnaire. Baseline body weight and height was measured in all the subjects along with checking of BCG (Bacillus Calmette–Guerin) scars. Details of smoking, alcoholism, substance abuse, family history of TB, etc., were also collected.

Biological samples

Approximately 6–8 ml of peripheral venous blood was obtained aseptically in the ethylenediaminetetraacetic acid vials from all the study subjects for molecular study/genomic DNA) extraction.

Molecular techniques and protocols

DNA extraction

Genomic DNA was extracted from peripheral blood using a DNA blood maxi kit (QIAamp, Qiagen, Germany). All centrifugation steps were carried out at 15°C–25°C. The protocol was used as per the manufacturer's instructions.

Determination of DNA concentration

The quantification of genomic DNA was carried out using optical density (OD) measurement of 1 ul of DNA at a wavelength of 260 nm and 280 nm using an ultraviolet nanophotometer. Pure DNA preparation gave OD 260/OD 280 ratio of 1.8–2. The OD value at 260 nm was used to calculate the concentration of DNA considering that 1 OD at 260 nm is equivalent to 50 ug DNA.

The DNA was also checked for fragmentation by electrophoresis on 0.8% agarose gel stained with ethidium bromide (EtBr) . For daily use, DNA was stored at 4°C, and for long-term storage, it was preserved at −80°C.

Genotyping for the TLR polymorphisms

The TLR genotypes for TLR2, TLR4, and TLR9 genes were assessed using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis by a Eppendorf thermocycler for PCR amplification (Eppendorf AG 22331, Hamburg, Germany).

Statistical analysis

Baseline characteristics (age and body mass index [BMI]) were compared among the groups using one-way analysis of variance followed by post hoc test with Bonferroni correction. The data were presented as mean ± standard deviation/median (interquartile range). Qualitative characteristics such as genotypic and allelic frequencies were compared using Chi-square (χ2) test. All analyses were performed using Stata version 12.0 (Stata Corporation, College Station, TX, USA). Two-sided P < 0.05 was considered statistically significant.


  Results Top


This study was undertaken to investigate the genetic variability in TLRs (TLR2, TLR4, and TLR9) among HIV-1-infected patients with and without TB coinfection. Five different study groups (HIV + patients, HIV + LTBI patients, HIV + TB patients, PTB Cat I patients, and healthy subjects) were genotyped for three SNPs (in TLR2, TLR4, and TLR9) followed by comparative analyses.

Baseline characteristics of the recruited study subjects

The demographic and baseline characteristics of the five study groups recruited in the study are provided in [Table 1]. There were 223 HIV + patients (mean age: 33 ± 7.7 years; 127 males and 96 females), 150 HIV + LTBI patients (mean age: 32 ± 8.1 years; 89 males and 61 females), 150 HIV + TB patients (mean age: 35 ± 7.2 years, 121 males and 29 females), 200 newly diagnosed PTB Cat I patients (mean age: 28 ± 2.4 years, 142 males and 58 females), and 205 healthy subjects (mean age: 36 ± 2.04 years, 140 males and 65 females).
Table 1: Comparison of baseline characteristics of study subjects

Click here to view


The BMI of various subgroups is provided in [Table 2]. It was observed that PTB Cat I patients were mildly underweight (17.2 ± 2.5), while HIV + TB patients were severely malnourished/underweight (15.6 ± 1.4) (P < 0.001) as per the WHO classification of BMI (WHO Expert Consultation, 2004).
Table 2: Comparison of toll-like receptor 4 aspartate 299 glycine (adenine 896 guanine, rs4986790) allelic frequencies between healthy subjects and patient groups

Click here to view


All HIV + LTBI patients were TST positive, performed by 5 TU, PPD (SPAN Diagnostics Ltd, Surat, India). Induration >5 mm was considered a positive reaction.

One hundred and fifty HIV + TB patients were classified into definitive (80 [53%]) and probable TB cases (70 [47%]) as per the definition provided earlier (Karmakar et al. 2011).

Of 80 definitive TB cases, 35 had PTB (20 were M. tuberculosis sputum smear positive, 10 patients were M. tuberculosis sputum smear and culture positive, and 5 patients were Mycobacterium tuberculosis M. tuberculosis smear positive for BAL) and the remaining 45 had EPTB. Of 45 EPTB cases, 26 had PE (either M. tuberculosis smear, M. tuberculosis smear, and culture or M. tuberculosis PCR positive), 4 had MTB (M. tuberculosis smear positive), and 15 patients had LNTB (FNAC proven).

Of 70 probable TB cases, 26 had PTB (CECT chest suggestive) and the remaining 44 patients had EPTB. Of 44 EPTB cases, 25 had LNTB (CECT chest suggestive), 16 had DTB (CECT chest + abdomen suggestive), and 3 had MTB (CT and chest-X-ray suggestive). In MTB patients, BAL smear and culture was negative for M. tuberculosis and transbronchial biopsy was also negative.

All HIV-negative PTB Cat I patients were newly diagnosed sputum smear positive cases. Since TB diagnosis was confirmed in all the cases, they were termed as definitive TB cases. M. tuberculosis culture was positive among 79% of the patients. Radiographic disease severity among PTB patients was determined by the National Diagnostic Standards and Classification of Tuberculosis. New York: National TB Association, 1961. As per the classification, 26 (13%) patients had minimal disease, 116 (58%) patients had moderately advanced disease, and 58 (29%) patients had far advanced disease.

Analysis of TLR2, TLR4, and TLR9 allelic and genotype frequencies in different study groups

The TLR2 allelic frequencies were observed among healthy subjects and patient groups (HIV + patients, HIV + LTBI patients, HIV + TB patients, and PTB Cat I patients). No statistically significant difference was observed in C2180T allele frequencies among healthy versus patient subcategories studied. Similarly, further comparison of TLR2 alleles (2180 C/T) within different patient groups also did not reveal any differences that were statistically significant.

No statistically significant difference in TLR2 genotype frequencies was observed between healthy subjects (CC 1.95% and CT 98.05%) and different patient groups [HIV+ (CC 2.7% and CT 97.3%), HIV + LTBI (CC 0% and CT 100%), HIV + TB (CC 2% and CT 98%), and PTB Cat I patients (CC 0% and CT 100%)].

Similarly, a comparison of TLR4 allelic frequencies between healthy subjects and patient groups was carried out. A statistically significant difference in TLR4 allelic frequencies was observed between HIV + TB patients (A 78.67% and G 21.33%) and healthy subjects (A 89.02% and G 10.98%), P < 0.001 [Table 2].

Similarly, TLR4 allelic frequencies were found to be significantly different between PTB Cat I patients (A 81.5% and G 18.5%) and healthy subjects (A 89.02% and G 10.98%), P < 0.003 [Table 2].

Further analysis of TLR4 allelic frequencies between different patient groups [Table 3] revealed that TLR4 allelic frequencies were significantly different between HIV + TB patients (A 78.67% and G 21.33%) and HIV + patients (A 85.20% and G 14.80%), P = 0.03.
Table 3: Comparison of toll-like receptor 4 aspartate 299 glycine (adenine 896 guanine, rs4986790) allelic frequencies within different patient groups

Click here to view


[Table 4] provides a comparison of TLR4 genotypes between healthy subjects and patient groups. A significant decrease in frequency of 'AA' genotype was observed in HIV + TB patients (62%) as compared to healthy subjects (78.05%). On the contrary, the AG and GG genotypes were significantly increased among HIV + TB patients (33.33% and 4.67%) versus 21.95% and 0% in healthy controls, respectively (P < 0.002). The GG genotype was exclusively found in HIV + TB group (4.67%).
Table 4: Comparison of toll-like receptor 4 aspartate 299 glycine (adenine 896 guanine, rs4986790) genotype frequencies between healthy subjects and patient groups

Click here to view


The TLR4 (AA and AG) genotypic frequencies were found to be significantly different between PTB Cat I patients (AA 63% and AG 37%) and healthy subjects (AA 78.05% and AG 21.95%), (P < 0.001).

TLR4 genotype frequencies between different patient groups are shown in [Table 5]. A significantly increased frequency of 'GG' genotype (4.67%) was observed exclusively in HIV + TB patients as compared to 0% in HIV+ (P < 0.002), HIV + LTBI, (P = 0.01), and PTB Cat I patients (P < 0.007).
Table 5: Comparison of toll-like receptor 4 aspartate 299 glycine (adenine 896 guanine, rs4986790) genotype frequencies within different patient groups

Click here to view


No statistically significant difference was observed in frequency distribution of TLR9 (1635A/G) alleles between healthy subjects (A 47.56% and G 52.44%) and various patient groups [HIV+ (A 43.27% and 56.73%), HIV + LTBI (A 44% and G 56%), HIV + TB (A 49.67% and G 5.33%), and PTB Cat I patients (A 50.5% and G 49.5%)]. However, a mild significant difference was observed in TLR9 allelic frequencies between PTB Cat I patients (A 50.5% and G 49.5%) and HIV + patients (A 43.27% and G 56.73%) (P = 0.04).

A comparison of TLR9 genotype frequencies between healthy subjects and patient groups is given in [Table 6]. A modest increase in the frequency of 'AA' genotype was observed in healthy subjects (28.78%) as compared to HIV + patients (19.73%), P = 0.05. The heterozygous 'AG' genotype was observed more frequently among HIV + TB (50%) and PTB Cat I (49%) patient groups as compared to healthy subjects (37.56%) (P = 0.05).
Table 6: Comparison of toll-like receptor 9 (1635 adenine/glycine, rs352140) genotype frequencies between healthy subjects and patient groups

Click here to view



  Discussion Top


TLRs, as key component of innate immune system, have the capability to sense the invading pathogen through differential recognition of PAMPs. They are responsible for eliciting innate immune effectors through production of inflammatory cytokines. The triggering of TLRs leads to stimulation of TLR-induced transcription factor, NF-kB, and activation of adaptive immunity of the host.[15],[16]

Studies have proposed that TLR2 polymorphisms were involved in bacterial infections and various diseases.[17] Xue et al. demonstrated that TLR2 and TLR4 were associated with pulmonary TB in the Tibetan population.[18] It has been found that functional polymorphism in TLR 2 and TLR4 was associated with many infections and diseases, including rheumatoid arthritis,[19] periodontitis, and sepsis.[20] A previous study on an Argentinean population showed the association of TLR2 Arg753Gln SNP with leptospirosis.[21]

However, it is interesting to note that majority of genetic studies available focused on patients and cohorts of Western ancestry, which is in striking contrast with the Indian population, characterized primarily by the presence of HIV clade C virus. The genetic factors significantly varying among and between different ethnic groups highlighted the importance and a strong need for specific population-based case–control studies to be conducted in HIV-infected patients of Indian ethnic origin. Therefore, it was planned to investigate the role of SNPs in TLRs in susceptibility to HIV and TB in ethnically homogenous ART and ATT naïve HIV-positive patients representing the North Indian population.

The findings of the present study indicate that TLR2 polymorphism does not influence individual susceptibility toward M. tuberculosis infection, TB disease, and HIV infection in Indian ethnic population. The results are consistent with the findings of the previous study from Indian subcontinent that demonstrated lack of TLR2 polymorphism in TB prevalent population.[22] These findings suggest that TLR2 polymorphism has no role in susceptibility to TB and HIV in an Indian ethnic population.

It has been discovered that the presence of Asp299Gly polymorphism within TLR4 gene leads to substitution of aspartic acid with glycine at position 299, which eventually results in altered TLR4 extracellular domain.[23] Our study demonstrated the potential role of TLR4 Asp299Gly polymorphism in increased susceptibility to TB among both HIV-negative and HIV-seropositive individuals.


  Conclusion Top


TLRs, as a key component of innate immune system, have the capability to sense the invading pathogen through differential recognition of PAMPs. They are responsible for eliciting innate immune effectors through production of inflammatory cytokines.[24] The triggering of TLRs leads to stimulation of TLR-induced transcription factor, NF-kB, and activation of adaptive immunity of the host.[15],[16]

Studies have demonstrated that mutations in TLRs influence signal transduction molecules, resulting in increased or decreased susceptibility to various bacterial and viral infections.[25] Several studies have also highlighted the association between TLR polymorphisms and increased susceptibility or protection against several ID.[26],[27],[28]

However, it is interesting to note that majority of genetic studies available focused on patients and cohorts of Western ancestry, which is in striking contrast with the Indian population, characterized primarily by the presence of HIV clade C virus. The genetic factors significantly varying among and between different ethnic groups highlighted the importance and a strong need for specific population-based case–control studies to be conducted in HIV-infected patients of Indian ethnic origin. Therefore, it was planned to investigate the role of SNPs in TLRs in susceptibility to HIV and TB in ethnically homogenous ART and ATT naïve HIV-positive patients representing the North Indian population.

The findings of the present study demonstrate the association of TLR4 Asp299Gly polymorphism with increased susceptibility to active TB among HIV-seropositive patients. These findings indicate the potential role of TLR4 polymorphism in attenuating the response to PAMPs and facilitating altered signaling pathway, leading to increased susceptibility to the development of serious infections such as TB.

Limitations of study

The study was limited to only investigate the genetic variability in TLR2, TLR4, and TLR9 and not all TLRs were included in the study due to the limited resources available. However, further studies are proposed to investigate the role of other TLRs in HIV-TB diseases pathogenesis and progression.

Ethical clearance

The study was approved by the Institutional Ethics Committee of the All India Institute of Medical Sciences (AIIMS), New Delhi (Ref. No.:A-35/05.05.2008).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Global Report: UNAIDS Report on the Global AIDS Epidemic. 2020.  Back to cited text no. 1
    
2.
NACO Report 2019. HIV Facts & Figures. NACO; 2019.  Back to cited text no. 2
    
3.
World Health Organization. Global Tuberculosis Report; 2021.  Back to cited text no. 3
    
4.
WHO. Global Tuberculosis Report; 2019.  Back to cited text no. 4
    
5.
Manabe YC, Bishai WR. Latent Mycobacterium tuberculosis-persistence, patience, and winning by waiting. Nat Med 2000;6:1327-9.  Back to cited text no. 5
    
6.
Rothel JS, Andersen P. Diagnosis of latent Mycobacterium tuberculosis infection: Is the demise of the Mantoux test imminent? Expert Rev Anti Infect Ther 2005;3:981-93.  Back to cited text no. 6
    
7.
Ahmed R, Gray D. Immunological memory and protective immunity: Understanding their relation. Science 1996;272:54-60.  Back to cited text no. 7
    
8.
O'Brien SJ, Nelson GW. Human genes that limit AIDS. Nat Genet 2004;36:565-74.  Back to cited text no. 8
    
9.
Kaur G, Mehra N. Genetic determinants of HIV-1 infection and progression to AIDS: Susceptibility to HIV infection. Tissue Antigens 2009;73:289-301.  Back to cited text no. 9
    
10.
Janeway CA Jr. Presidential address to the American Association of Immunologists. The road less traveled by: The role of innate immunity in the adaptive immune response. J Immunol 1998;161:539-44.  Back to cited text no. 10
    
11.
Takeuchi O, Akira S. MDA5/RIG-I and virus recognition. Curr Opin Immunol 2008;20:17-22.  Back to cited text no. 11
    
12.
Bowie AG, Haga IR. The role of Toll-like receptors in the host response to viruses. Mol Immunol 2005;42:859-67.  Back to cited text no. 12
    
13.
Imler JL, Hoffmann JA. Toll receptors in innate immunity. Trends Cell Biol 2001;11:304-11.  Back to cited text no. 13
    
14.
Barton GM. Viral recognition by Toll-like receptors. Semin Immunol 2007;19:33-40.  Back to cited text no. 14
    
15.
Kawai T, Akira S. Toll-like receptor downstream signaling. Arthritis Res Ther 2005;7:12-9.  Back to cited text no. 15
    
16.
Báfica A, Scanga CA, Schito M, Chaussabel D, Sher A. Influence of coinfecting pathogens on HIV expression: Evidence for a role of Toll-like receptors. J Immunol 2004;172:7229-34.  Back to cited text no. 16
    
17.
Alvarez AE, Marson FA, Bertuzzo CS, Bastos JC, Baracat EC, Brandão MB, et al. Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis. Gene 2018;645:7-17.  Back to cited text no. 17
    
18.
Xue X, Qiu Y, Jiang D, Jin T, Yan M, Zhu X, et al. The association analysis of TLR2 and TLR4 gene with tuberculosis in the Tibetan Chinese population. Oncotarget 2017;8:113082-9.  Back to cited text no. 18
    
19.
Yang H, Wei C, Li Q, Shou T, Yang Y, Xiao C, et al. Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis in Chinese Han population. Rheumatol Int 2013;33:1283-8.  Back to cited text no. 19
    
20.
Wang H, Wei Y, Zeng Y, Qin Y, Xiong B, Qin G, et al. The association of polymorphisms of TLR4 and CD14 genes with susceptibility to sepsis in a Chinese population. BMC Med Genet 2014;15:123.  Back to cited text no. 20
    
21.
Cédola M, Chiani Y, Pretre G, Alberdi L, Vanasco B, Gómez RM. Association of Toll-like receptor 2 Arg753Gln and Toll-like receptor 1 Ile602Ser single-nucleotide polymorphisms with leptospirosis in an Argentine population. Acta Trop 2015;146:73-80.  Back to cited text no. 21
    
22.
Biswas D, Gupta SK, Sindhwani G, Patras A. TLR2 polymorphisms, Arg753Gln and Arg677Trp, are not associated with increased burden of tuberculosis in Indian patients. BMC Res Notes 2009;2:162.  Back to cited text no. 22
    
23.
Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000;25:187-91.  Back to cited text no. 23
    
24.
Medzhitov R, Janeway CA Jr. How does the immune system distinguish self from nonself? Semin Immunol 2000;12:185-8.  Back to cited text no. 24
    
25.
Schröder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 2005;5:156-64.  Back to cited text no. 25
    
26.
Ogus AC, Yoldas B, Ozdemir T, Uguz A, Olcen S, Keser I, et al. The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 2004;23:219-23.  Back to cited text no. 26
    
27.
Tal G, Mandelberg A, Dalal I, Cesar K, Somekh E, Tal A, et al. Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J Infect Dis 2004;189:2057-63.  Back to cited text no. 27
    
28.
Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaires' disease. J Exp Med 2003;198:1563-72.  Back to cited text no. 28
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed480    
    Printed20    
    Emailed0    
    PDF Downloaded55    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]