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The TLR5 1174C>T Polymorphism in Melioidosis Infection

The TLR5 1174C>T Polymorphism in Melioidosis Infection. Chief of Medicine Conference 10/2/12 Presented by Amy Dickey, MD R2, Internal Medicine Principal Investigator: Eoin West, MD MPH. Outline. Background: What is m elioidosis ? What are Toll Like Receptors?

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The TLR5 1174C>T Polymorphism in Melioidosis Infection

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  1. The TLR51174C>T Polymorphism in Melioidosis Infection Chief of Medicine Conference 10/2/12 Presented by Amy Dickey, MD R2, Internal Medicine Principal Investigator: Eoin West, MD MPH

  2. Outline • Background: • What is melioidosis? • What are Toll Like Receptors? • How is the TLR51174C>T polymorphism important in mortality from melioidosis? • Hypothesis– Defining the role of the TLR51174C>T polymorphism in cell signaling. • Data • Conclusions and future directions

  3. Melioidosis • Melioidosis– the disease caused by the pathogen Burkholderiapseudomallei • An important cause of pneumonia and sepsis in SE Asia and northern Australia. • The mortality rate from melioidosis can reach 40%. Figure 1. The global distribution of Melioidosis. NEJM Sept 13, 2012.

  4. Flagellin is the TLR5 agonist • Toll Like Receptors are signaling receptors of the innate immune system. • They recognize molecules shared by pathogens called pathogen-associated molecular patterns (PAMPs). • Important antigens containing PAMPs include LPS, flagellin, and lipopeptides Figure 2: Toll like receptor signaling pathways

  5. The TLR51174C>T non-functional polymorphism improves survival from melioidosis. • The TLR51174C>T polymorphism encodes a premature stop codon in the ligand-binding domain of TLR5. • In a cohort of Thai melioidosis patients, those with the TLR51174C>Tpolymorphism experienced a 3x decrease in in-hospital mortality from melioidosisinfection. TLR5 TLR5 mutant Table 1: TLR51174C>T genotype and in-hospital mortality

  6. Surprisingly, the TLR51174C>T polymorphism modulates cytokine response to both flagellin and LPS. Figure 4. IL-8 expression Figure 3. GCSF expression

  7. Hypothesis • TLR51174C>T polymorphism modulates the TLR4-dependent innate immune response to B. pseudomallei. LPS TLR5 TLR4 TLR5 mutant ? ? NF-kB Inflammatory Cytokines

  8. The TLR51174C>T polymorphism increases NF-kB expression in response to LPS. Figure 6. NF-kB activation

  9. Surprisingly, the TLR5 polymorphism increases NF-kB expression but decreases IL8 expression in response to LPS. Figure 7. NF-kB activation Figure 8. IL-8 expression

  10. The TLR51174C>T polymorphism attenuates IL8 expression in response to B. pseudomallei, an effect independent of flagellin. Figure 9: IL-8 expression assay

  11. Conclusion • Conclusion: TLR51174C>T polymorphism modulates the TLR4-dependent innate immune response to Burkholderiapseudomallei. Specifically, the TLR51174C>T polymorphism alters TLR4-dependent NF-kB activation and IL-8 expression. • Additional Questions: Does the mutant TLR5 or the wild type TLR5 modulate TLR4-dependent signaling? At what level does it modulate signaling? LPS TLR5 TLR4 TLR5 mutant NF-kB Inflammatory Cytokines

  12. Acknowledgements The West Lab • Eoin West, MD MPH • Sudeshna Seal, PhD • Johanna Robertson Members of the Wurfel and Skerrett labs.

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