A Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human Melioidosis
Background<br/> Melioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. Toll-like receptor (TLR) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. We evaluated the association of...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
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Public Library of Science
2017
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| _version_ | 1797058668929220608 |
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| author | Chaichana, P Chantratita, N Brod, F Koosakulnirand, S Jenjaroen, K Chumseng, S Sumonwiriya, M Burtnick, M Brett, P Teparrukkul, P Limmathurotsakul, D Day, N Dunachie, S West, T |
| author_facet | Chaichana, P Chantratita, N Brod, F Koosakulnirand, S Jenjaroen, K Chumseng, S Sumonwiriya, M Burtnick, M Brett, P Teparrukkul, P Limmathurotsakul, D Day, N Dunachie, S West, T |
| author_sort | Chaichana, P |
| collection | OXFORD |
| description | Background<br/> Melioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. Toll-like receptor (TLR) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. We evaluated the association of a nonsense TLR5 genetic variant that truncates the receptor with clinical outcomes and with immune responses in melioidosis. <br/><br/>Methodology/Principle Findings<br/> We genotyped TLR5 c.1174C>T in 194 acute melioidosis patients in Thailand. Twenty-six (13%) were genotype CT or TT. In univariable analysis, carriage of the c.1174C>T variant was associated with lower 28-day mortality (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05-0.94, P = 0.04) and with lower 90-day mortality (OR 0.25, 95% CI 0.07-086, P = 0.03). In multivariable analysis adjusting for age, sex, diabetes and renal disease, the adjusted OR for 28-day mortality in carriers of the variant was 0.24 (95% CI 0.05-1.08, P = 0.06); and the adjusted OR for 90-day mortality was 0.27 (95% CI 0.08-0.97, P = 0.04). c.1174C>T was associated with a lower rate of bacteremia (P = 0.04) and reduced plasma levels of IL-10 (P = 0.049) and TNF-α (P < 0.0001). We did not find an association between c.1174C>T and IFN-γ ELISPOT (T-cell) responses (P = 0.49), indirect haemagglutination titers or IgG antibodies to bacterial flagellin during acute melioidosis (P = 0.30 and 0.1, respectively). <br/><br/>Conclusions/Significance<br/> This study independently confirms the association of TLR5 c.1174C>T with protection against death in melioidosis, identifies lower bacteremia, IL-10 and TNF-α production in carriers of the variant with melioidosis, but does not demonstrate an association of the variant with acute T-cell IFN-γ response, indirect haemagglutination antibody titer, or anti-flagellin IgG antibodies. |
| first_indexed | 2024-03-06T19:53:32Z |
| format | Journal article |
| id | oxford-uuid:24c7d1cb-2842-42e6-b645-ce5764b52ff4 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T19:53:32Z |
| publishDate | 2017 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:24c7d1cb-2842-42e6-b645-ce5764b52ff42022-03-26T11:52:01ZA Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human MelioidosisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:24c7d1cb-2842-42e6-b645-ce5764b52ff4Symplectic Elements at OxfordPublic Library of Science2017Chaichana, PChantratita, NBrod, FKoosakulnirand, SJenjaroen, KChumseng, SSumonwiriya, MBurtnick, MBrett, PTeparrukkul, PLimmathurotsakul, DDay, NDunachie, SWest, TBackground<br/> Melioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. Toll-like receptor (TLR) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. We evaluated the association of a nonsense TLR5 genetic variant that truncates the receptor with clinical outcomes and with immune responses in melioidosis. <br/><br/>Methodology/Principle Findings<br/> We genotyped TLR5 c.1174C>T in 194 acute melioidosis patients in Thailand. Twenty-six (13%) were genotype CT or TT. In univariable analysis, carriage of the c.1174C>T variant was associated with lower 28-day mortality (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05-0.94, P = 0.04) and with lower 90-day mortality (OR 0.25, 95% CI 0.07-086, P = 0.03). In multivariable analysis adjusting for age, sex, diabetes and renal disease, the adjusted OR for 28-day mortality in carriers of the variant was 0.24 (95% CI 0.05-1.08, P = 0.06); and the adjusted OR for 90-day mortality was 0.27 (95% CI 0.08-0.97, P = 0.04). c.1174C>T was associated with a lower rate of bacteremia (P = 0.04) and reduced plasma levels of IL-10 (P = 0.049) and TNF-α (P < 0.0001). We did not find an association between c.1174C>T and IFN-γ ELISPOT (T-cell) responses (P = 0.49), indirect haemagglutination titers or IgG antibodies to bacterial flagellin during acute melioidosis (P = 0.30 and 0.1, respectively). <br/><br/>Conclusions/Significance<br/> This study independently confirms the association of TLR5 c.1174C>T with protection against death in melioidosis, identifies lower bacteremia, IL-10 and TNF-α production in carriers of the variant with melioidosis, but does not demonstrate an association of the variant with acute T-cell IFN-γ response, indirect haemagglutination antibody titer, or anti-flagellin IgG antibodies. |
| spellingShingle | Chaichana, P Chantratita, N Brod, F Koosakulnirand, S Jenjaroen, K Chumseng, S Sumonwiriya, M Burtnick, M Brett, P Teparrukkul, P Limmathurotsakul, D Day, N Dunachie, S West, T A Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human Melioidosis |
| title | A Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human Melioidosis |
| title_full | A Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human Melioidosis |
| title_fullStr | A Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human Melioidosis |
| title_full_unstemmed | A Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human Melioidosis |
| title_short | A Nonsense Mutation in TLR5 Is Associated with Survival and Reduced IL-10 and TNF-α Levels in Human Melioidosis |
| title_sort | nonsense mutation in tlr5 is associated with survival and reduced il 10 and tnf α levels in human melioidosis |
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