Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis
Abstract
:1. Introduction
2. Results
2.1. Cohort Characteristics and Genotyping
2.2. Docking Outcome
2.3. Mass Spectrometry
2.4. Co-Immunoprecipitation
2.5. Co-Localisation
2.6. Functional Studies
3. Discussion
4. Materials and Methods
4.1. Study Subjects
4.2. SNP Analysis
4.3. Modelling and Molecular Docking
4.4. In Vitro Experiments
4.4.1. Stimulants and Reagents
4.4.2. Mutagenesis
4.4.3. Cell Line Experiments
4.4.4. Transient Transfection
4.4.5. Immunofluorescence Staining of TLR8HA/Confocal Microscopy
4.4.6. Co-Immunoprecipitation
4.4.7. Western Blot Procedure
4.5. Mass Spectrometry (MS)
4.5.1. Sample Preparation
4.5.2. Mass Spectrometric and Statistical Analysis
4.6. PBMC Experiments
4.7. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
A | Adenine |
APC | Antigen-presenting cell |
ARDS | acute respiratory distress syndrome |
BCG | Bacillus Calmette–Guérin |
BMI | Body mass index |
BSA | Bovine serum albumin |
C | Cytosine |
DC | Dendritic cell |
DMEM | Dulbecco’s Modified Eagle’s Medium |
ELISA | Enzyme-linked immunosorbent assay |
EPTB | Extrapulmonary TB |
FCS | Fetal calf serum |
G | Guanine |
HA | Human influenza hemagglutinin |
HC | Healthy control |
HEK | Human embryonic kidney |
HHC | Healthy household contact |
IFN | Interferon |
IL | Interleukin |
IP | Immunoprecipitation |
IRF | Interferon response factor |
LAM | Lipoarabinomannan |
LM | Lipomannan |
LPS | Lipopolysaccharide |
LRT | Likelihood ratio test |
MHC | Major histocompatibility complex |
Mtb | Mycobacerium tuberculosis |
MyD88 | Myeloid differentiation primary response 88 |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
PAMP | Pathogen-associated molecular pattern |
PMB | Polymyxin B |
PRR | Pattern recognition receptor |
PTB | Pulmonary TB |
SEAP | Secreted embryonic alkaline phosphatase |
T | Thymine |
TB | Tuberculosis |
Th | T helper |
TLR | Toll-like receptor |
TNF | Tumour necrosis factor |
TRAM | TRIF-related adaptor molecule |
TRIF | TIR-domain-containing adapter-inducing interferon-β |
WB | Western blotting |
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TLR SNPs (Nucleotide Change) | Alleles | N | Allele Frequency [N(%)] Controls Primary TB | OR [95% CI] * | p-Value | |
---|---|---|---|---|---|---|
TLR4-Asp299Gly (A > G) | G | 533 | 72 (27.48) | 100 (33.22) | 0.72 [0.49–1.07] | 0.101 |
TLR4-Thr399Ile (C > T) | T | 552 | 68 (23.37) | 105 (31.44) | 1.57 [1.04–2.36] | 0.027 |
TLR8-Met1Val (A > G) | A | 556 | 139 (47.60) | 199 (58.70) | 1.68 [1.08–2.63] | 0.022 |
TLR8-1, when TLR4-399CT/T | A | 395 | 34 (50.00) | 59 (56.19) | 1.97 [1.15–3.37] | 0.013 |
TLR8-1, when TLR4-399CC | A | 155 | 105 (47.09) | 137 (59.83) | 1.19 [0.52–2.72] | 0.681 |
TLR SNPs | Alleles | N | Allele Frequency [N(%)] Primary TB Relapses | OR [95% CI] * | p-Value | |
---|---|---|---|---|---|---|
TLR4-Asp299Gly | G | 383 | 100 (33.22) | 36 (39.13) | 0.80 [0.49–1.32] | 0.381 |
TLR4-Thr399Ile | T | 376 | 105 (31.44) | 33 (38.82) | 1.36 [0.81–2.28] | 0.242 |
TLR8-Met1Val | A | 355 | 140 (58.70) | 68 (72.34) | 1.99 [1.03–3.82] | 0.035 |
TLR8-1, when TLR4-399CT/T | A | 111 | 59 (56.19) | 25 (75.76) | 2.90 [0.87–9.59] | 0.069 |
TLR8-1, when TLR4-399CC | A | 231 | 137 (59.82) | 37 (71.15) | 1.62 [0.69–3.81] | 0.265 |
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Thada, S.; Horvath, G.L.; Müller, M.M.; Dittrich, N.; Conrad, M.L.; Sur, S.; Hussain, A.; Pelka, K.; Gaddam, S.L.; Latz, E.; et al. Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis. Int. J. Mol. Sci. 2021, 22, 1560. https://doi.org/10.3390/ijms22041560
Thada S, Horvath GL, Müller MM, Dittrich N, Conrad ML, Sur S, Hussain A, Pelka K, Gaddam SL, Latz E, et al. Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis. International Journal of Molecular Sciences. 2021; 22(4):1560. https://doi.org/10.3390/ijms22041560
Chicago/Turabian StyleThada, Shruthi, Gabor L. Horvath, Mario M. Müller, Nickel Dittrich, Melanie L. Conrad, Saubashya Sur, Abid Hussain, Karin Pelka, Suman Latha Gaddam, Eicke Latz, and et al. 2021. "Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis" International Journal of Molecular Sciences 22, no. 4: 1560. https://doi.org/10.3390/ijms22041560