Impaired TLR5 functionality is associated with survival in melioidosis.
Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR5(1174C)>T, to elucidate the role of TLR5 in melioidosis. W...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2013
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| _version_ | 1797099937079492608 |
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| author | West, T Chantratita, N Chierakul, W Limmathurotsakul, D Wuthiekanun, V Myers, N Emond, M Wurfel, M Hawn, T Peacock, S Skerrett, S |
| author_facet | West, T Chantratita, N Chierakul, W Limmathurotsakul, D Wuthiekanun, V Myers, N Emond, M Wurfel, M Hawn, T Peacock, S Skerrett, S |
| author_sort | West, T |
| collection | OXFORD |
| description | Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR5(1174C)>T, to elucidate the role of TLR5 in melioidosis. We measured NF-κB activation induced by B. pseudomallei in human embryonic kidney-293 cells transfected with TLR5 and found that B. pseudomallei induced TLR5(1174C)- but not TLR5(1174T)-dependent activation of NF-κB. We tested the association of TLR5(1174C)>T with outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR5(1174C)>T was associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08-0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR5(1174C)>T genotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-α, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1β in carriers of TLR5(1174T) compared with carriers of TLR5(1174C). B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR5(1174T). We conclude that the hypofunctional genetic variant TLR5(1174C)>T is associated with reduced organ failure and improved survival in melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in melioidosis. |
| first_indexed | 2024-03-07T05:30:35Z |
| format | Journal article |
| id | oxford-uuid:e222360e-ca71-4a0e-a1d6-eb04b5f9a4f7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:30:35Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:e222360e-ca71-4a0e-a1d6-eb04b5f9a4f72022-03-27T09:58:58ZImpaired TLR5 functionality is associated with survival in melioidosis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e222360e-ca71-4a0e-a1d6-eb04b5f9a4f7EnglishSymplectic Elements at Oxford2013West, TChantratita, NChierakul, WLimmathurotsakul, DWuthiekanun, VMyers, NEmond, MWurfel, MHawn, TPeacock, SSkerrett, SMelioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR5(1174C)>T, to elucidate the role of TLR5 in melioidosis. We measured NF-κB activation induced by B. pseudomallei in human embryonic kidney-293 cells transfected with TLR5 and found that B. pseudomallei induced TLR5(1174C)- but not TLR5(1174T)-dependent activation of NF-κB. We tested the association of TLR5(1174C)>T with outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR5(1174C)>T was associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08-0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR5(1174C)>T genotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-α, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1β in carriers of TLR5(1174T) compared with carriers of TLR5(1174C). B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR5(1174T). We conclude that the hypofunctional genetic variant TLR5(1174C)>T is associated with reduced organ failure and improved survival in melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in melioidosis. |
| spellingShingle | West, T Chantratita, N Chierakul, W Limmathurotsakul, D Wuthiekanun, V Myers, N Emond, M Wurfel, M Hawn, T Peacock, S Skerrett, S Impaired TLR5 functionality is associated with survival in melioidosis. |
| title | Impaired TLR5 functionality is associated with survival in melioidosis. |
| title_full | Impaired TLR5 functionality is associated with survival in melioidosis. |
| title_fullStr | Impaired TLR5 functionality is associated with survival in melioidosis. |
| title_full_unstemmed | Impaired TLR5 functionality is associated with survival in melioidosis. |
| title_short | Impaired TLR5 functionality is associated with survival in melioidosis. |
| title_sort | impaired tlr5 functionality is associated with survival in melioidosis |
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