Melioidosis is an often lethal emerging infectious disease caused by the Gram-negative soil saprophyte and putative bioweapon, Burkholderia pseudomallei. Endemic in northeast Thailand, mortality exceeds 40%. The disease results from inhalation or cutaneous inoculation with B. pseudomallei and most frequently presents with pneumonia and sepsis. Pneumonia confers over a two-fold increase in the odds of death. Melioidosis is representative of the huge global burden of pneumonia and sepsis in low resource settings, for which new therapies are urgently needed. We have identified a key role for Toll-like receptor 5 (TLR5), a cell surface flagellin sensor, in melioidosis. TLR5-deficiency accelerates death from respiratory infection in mice but a common human genetic variant in TLR5 that encodes a non-functional receptor is associated with dramatically improved survival in hospitalized patients with melioidosis. The variant is also associated with lower pro- inflammatory cytokine responses to B. pseudomallei upon stimulation of blood ex vivo. Although the only known ligand of TLR5 is flagellin, the reduced cytokine responses in carriers of the genetic variant are independent of B. pseudomallei flagellin and are also observed in response to B. pseudomallei lipopolysaccharide, a TLR4 agonist. These intriguing preliminary genetic data necessitate additional study of the mechanisms underlying the effect of the TLR5 genetic variant and the flagellin-TLR5 axis in melioidosis. The contrasting murine and human phenotypes emphasize the importance of performing translational science in humans. We hypothesize that an excessive host inflammatory response to this lung-tropic organism, regulated by TLR5 but independent of flagellin sensing, contributes to organ dysfunction and death in melioidosis patients. We will leverage the PI's translational melioidosis research program and robust collaboration with Thai investigators to test this hypothesis in three inter-related ways: 1) Determine whether the TLR5 genetic variant is associated with blunted innate immune activation, reduced inflammatory responses, and improved clinical outcome in melioidosis patients, 2) determine how TLR5 regulates inflammatory responses to B. pseudomallei in the lung, and 3) determine whether differential signaling mediated by the TLR5 genetic variant in B. pseudomallei infection is independent of flagellin sensing. A better understanding of TLR5 in melioidosis will increase the potential for therapeutic interventions and have ramifications for other etiologies of pneumonia and sepsis worldwide.

Public Health Relevance

Pneumonia and sepsis are huge contributors to the global burden of disease, particularly in low resource settings. In this application, we propose to gain a better understanding of the immune response in melioidosis, a common cause of pneumonia and sepsis in rural Thailand. The findings from this work may help to develop therapies to alleviate this burden and improve the health of the public worldwide.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113382-02
Application #
8469901
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (03))
Program Officer
Eu, Jerry Pc
Project Start
2012-05-15
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$573,608
Indirect Cost
$148,627
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chantratita, N; Tandhavanant, S; Seal, S et al. (2016) TLR4 genetic variation is associated with inflammatory responses in Gram-positive sepsis. Clin Microbiol Infect :
Goss, Christopher H; VanDevanter, Donald R (2016) CFTR modulators and pregnancy: Our work has only just begun. J Cyst Fibros 15:6-7
Heltshe, Sonya L; Goss, Christopher H (2016) Optimising treatment of CF pulmonary exacerbation: a tough nut to crack. Thorax 71:101-2
Goss, Christopher H (2016) With Every Upside, There Is a Downside: Chest Radiation and Survivors of Childhood Cancers. Ann Am Thorac Soc 13:1448-9
Sack, Cora S; Goss, Christopher H (2016) Nature versus Nurture: Does Genetic Ancestry Alter the Effect of Air Pollution in Children with Asthma? Am J Respir Crit Care Med 193:1196-8
Goss, Louisa B; Ortiz, Justin R; Okamura, Daryl M et al. (2015) Significant Reductions in Mortality in Hospitalized Patients with Systemic Lupus Erythematosus in Washington State from 2003 to 2011. PLoS One 10:e0128920
Sack, Coralynn; Goss, Christopher H (2015) It Starts at the Beginning: Effect of Particulate Matter In Utero. Am J Respir Crit Care Med 192:1025-6
Goss, Christopher H; MacNeill, Stephanie J; Quinton, Hebe B et al. (2015) Children and young adults with CF in the USA have better lung function compared with the UK. Thorax 70:229-36
Quon, Bradley S; Goss, Christopher H; Ramsey, Bonnie W (2014) Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc 11:425-34
Ortiz, Justin R; Neuzil, Kathleen M; Shay, David K et al. (2014) The burden of influenza-associated critical illness hospitalizations. Crit Care Med 42:2325-32

Showing the most recent 10 out of 14 publications