Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis.
Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR51174C>T is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome i...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2014
|
| _version_ | 1797103300059856896 |
|---|---|
| author | Chantratita, N Tandhavanant, S Myers, N Chierakul, W Robertson, J Mahavanakul, W Singhasivanon, P Emond, M Peacock, S West, T |
| author_facet | Chantratita, N Tandhavanant, S Myers, N Chierakul, W Robertson, J Mahavanakul, W Singhasivanon, P Emond, M Peacock, S West, T |
| author_sort | Chantratita, N |
| collection | OXFORD |
| description | Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR51174C>T is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome in melioidosis. We genotyped 12 TLR5 variants selected de novo from the HapMap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy Thai subjects. We found a blunted cytokine response for three related markers that were in linkage disequilibrium (LD) with a non-synonymous variant, TLR51846T>C. Carriers of TLR51846T>C had broadly impaired cytokine responses induced by flagellin. TLR51846T>C was associated with protection against death in melioidosis patients (odds ratio: 0.62, 95% confidence interval: 0.42-0.93, P=0.021). We observed no impairment in TLR51846C-dependent nuclear factor κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR51846T>C was in strong LD with TLR51174C>T. Many of the blunted cytokine responses observed and the association of TLR51846T>C with survival in melioidosis patients may be attributable to TLR51174C>T, but we could not exclude an independent effect of TLR51846T>C. These data identify novel associations for TLR51846T>C, enhance our understanding of TLR5 genetic architecture in Thais and highlight the role of TLR5 in melioidosis. |
| first_indexed | 2024-03-07T06:18:09Z |
| format | Journal article |
| id | oxford-uuid:f1ca9786-b09b-47d0-bfc9-11d362e58755 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:18:09Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:f1ca9786-b09b-47d0-bfc9-11d362e587552022-03-27T11:58:42ZScreen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f1ca9786-b09b-47d0-bfc9-11d362e58755EnglishSymplectic Elements at OxfordNature Publishing Group2014Chantratita, NTandhavanant, SMyers, NChierakul, WRobertson, JMahavanakul, WSinghasivanon, PEmond, MPeacock, SWest, TMelioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR51174C>T is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome in melioidosis. We genotyped 12 TLR5 variants selected de novo from the HapMap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy Thai subjects. We found a blunted cytokine response for three related markers that were in linkage disequilibrium (LD) with a non-synonymous variant, TLR51846T>C. Carriers of TLR51846T>C had broadly impaired cytokine responses induced by flagellin. TLR51846T>C was associated with protection against death in melioidosis patients (odds ratio: 0.62, 95% confidence interval: 0.42-0.93, P=0.021). We observed no impairment in TLR51846C-dependent nuclear factor κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR51846T>C was in strong LD with TLR51174C>T. Many of the blunted cytokine responses observed and the association of TLR51846T>C with survival in melioidosis patients may be attributable to TLR51174C>T, but we could not exclude an independent effect of TLR51846T>C. These data identify novel associations for TLR51846T>C, enhance our understanding of TLR5 genetic architecture in Thais and highlight the role of TLR5 in melioidosis. |
| spellingShingle | Chantratita, N Tandhavanant, S Myers, N Chierakul, W Robertson, J Mahavanakul, W Singhasivanon, P Emond, M Peacock, S West, T Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis. |
| title | Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis. |
| title_full | Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis. |
| title_fullStr | Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis. |
| title_full_unstemmed | Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis. |
| title_short | Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis. |
| title_sort | screen of whole blood responses to flagellin identifies tlr5 variation associated with outcome in melioidosis |
| work_keys_str_mv | AT chantratitan screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT tandhavanants screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT myersn screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT chierakulw screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT robertsonj screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT mahavanakulw screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT singhasivanonp screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT emondm screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT peacocks screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis AT westt screenofwholebloodresponsestoflagellinidentifiestlr5variationassociatedwithoutcomeinmelioidosis |