The tlr5 1174c t polymorphism in melioidosis infection
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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

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


Outline
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


Melioidosis
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.


Flagellin is the tlr5 agonist
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


The tlr5 1174c t non functional polymorphism improves survival from melioidosis
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


Surprisingly the tlr5 1174c t polymorphism modulates cytokine response to both flagellin and lps
Surprisingly, the TLR51174C>T polymorphism modulates cytokine response to both flagellin and LPS.

Figure 4. IL-8 expression

Figure 3. GCSF expression


Hypothesis
Hypothesis

  • TLR51174C>T polymorphism modulates the TLR4-dependent innate immune response to B. pseudomallei.

LPS

TLR5

TLR4

TLR5 mutant

?

?

NF-kB

Inflammatory

Cytokines


The tlr5 1174c t polymorphism in melioidosis infection

The TLR51174C>T polymorphism increases NF-kB expression in response to LPS.

Figure 6. NF-kB activation


The tlr5 1174c t polymorphism in melioidosis infection

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


The tlr5 1174c t polymorphism in melioidosis infection
The TLR51174C>T polymorphism attenuates IL8 expression in response to B. pseudomallei, an effect independent of flagellin.

Figure 9: IL-8 expression assay


Conclusion
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


Acknowledgements
Acknowledgements

The West Lab

  • Eoin West, MD MPH

  • Sudeshna Seal, PhD

  • Johanna Robertson

    Members of the Wurfel and Skerrett labs.