Melioidosis is a tropical infection caused by inhalation, ingestion, or inoculation of the Gram-negative soil saprophyte and Tier 1 select agent Burkholderia pseudomallei. Although increasingly recognized throughout the tropics, melioidosis is hyperendemic in northeast Thailand, where it is tied as the second leading infectious cause of death. Even with appropriate antibiotic treatment, 40% of patients die, many from severe sepsis. Of survivors, about 10% relapse, most in the first year. As for other causes of sepsis, no successful immunomodulatory therapies exist. Melioidosis is therefore a major public health threat in Thailand for which new therapies are urgently needed. We have implemented a highly successful Thai-US collaboration to elucidate mechanisms of host defense in human melioidosis for nearly eight years. Our whole exome sequencing studies of bacteremic patients have identified candidate genes and inflammatory pathways that may determine outcome in melioidosis. Our collaborators on this proposal, Dr. Chaussabel and Dr. Lertmongkolchai, have analyzed the blood transcriptome to create signatures that distinguish melioidosis from other causes of sepsis and identify biological pathway activation that is unique to melioidosis. While the human inflammatory response in melioidosis remains poorly understood, our preliminary results spotlight the promise of the application of advanced technologies to melioidosis. We propose a Melioidosis ICIDR that intensifies existing international scientific relationships by applying state-of-the-art technologies to comprehensively elucidate the immunologic and inflammatory mechanisms underlying the pathogenesis of melioidosis and poor response to therapies. We will augment our whole exome sequencing analyses with whole transcriptome RNA sequencing and high-throughput single cell polychromatic flow cytometry for sophisticated immunophenotyping of melioidosis patients. Designed around a prospective, multi-center longitudinal cohort study of melioidosis with detailed clinical and biological phenotyping, and expert-supported in-country analysis of all resulting data, the proposal will directly enhance Thai melioidosis research capacity.
Our aims are to 1) identify host inflammatory changes in acute melioidosis that elucidate pathogenesis and predict death, 2) identify immunological mechanisms that permit relapse, and 3) validate newly identified genetic determinants of survival in melioidosis. Beyond the scientific aims addressed in this application, the proposal establishes a unique and durable melioidosis research platform headquartered in the optimal location for clinical melioidosis research, with tremendous potential to impact the public health o Thais and global citizens alike.

Public Health Relevance

Melioidosis is a tropical bacterial infection that is common and often lethal in northeast Thailand. Our objective is to understand the mechanisms underlying the poor responses to therapy. This knowledge may help identify new strategies for treatment and improve public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI115520-04
Application #
9421545
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Mukhopadhyay, Suman
Project Start
2015-02-10
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mahidol University
Department
Type
DUNS #
660984043
City
Nakhon Pathom
State
Country
Thailand
Zip Code
73170
Koosakulnirand, Sirikamon; Phokrai, Phornpun; Jenjaroen, Kemajittra et al. (2018) Immune response to recombinant Burkholderia pseudomallei FliC. PLoS One 13:e0198906
Phokrai, Phornpun; Karoonboonyanan, Wisansanee; Thanapattarapairoj, Nida et al. (2018) A Rapid Immunochromatography Test Based on Hcp1 Is a Potential Point-of-Care Test for Serological Diagnosis of Melioidosis. J Clin Microbiol 56:
Sengyee, Sineenart; Yoon, Sung Hwan; Paksanont, Suporn et al. (2018) Comprehensive analysis of clinical Burkholderia pseudomallei isolates demonstrates conservation of unique lipid A structure and TLR4-dependent innate immune activation. PLoS Negl Trop Dis 12:e0006287
Paksanont, Suporn; Sintiprungrat, Kitisak; Yimthin, Thatcha et al. (2018) Effect of temperature on Burkholderia pseudomallei growth, proteomic changes, motility and resistance to stress environments. Sci Rep 8:9167
Pumpuang, Apinya; Dunachie, Susanna J; Phokrai, Phornpun et al. (2017) Comparison of O-polysaccharide and hemolysin co-regulated protein as target antigens for serodiagnosis of melioidosis. PLoS Negl Trop Dis 11:e0005499
Pumirat, Pornpan; Vanaporn, Muthita; Boonyuen, Usa et al. (2017) Effects of sodium chloride on heat resistance, oxidative susceptibility, motility, biofilm and plaque formation of Burkholderia pseudomallei. Microbiologyopen 6:
Sengyee, Sineenart; Saiprom, Natnaree; Paksanont, Suporn et al. (2017) Susceptibility of Clinical Isolates of Burkholderia pseudomallei to a Lipid A Biosynthesis Inhibitor. Am J Trop Med Hyg 97:62-67
Tamigney Kenfack, Marielle; Mazur, Marcelina; Nualnoi, Teerapat et al. (2017) Deciphering minimal antigenic epitopes associated with Burkholderia pseudomallei and Burkholderia mallei lipopolysaccharide O-antigens. Nat Commun 8:115
Dulsuk, Adul; Paksanont, Suporn; Sangchankoom, Adisak et al. (2017) Validation of a monoclonal antibody-based immunofluorescent assay to detect Burkholderia pseudomallei in blood cultures. Trans R Soc Trop Med Hyg :
Muangsombut, Veerachat; Withatanung, Patoo; Srinon, Varintip et al. (2017) Burkholderia pseudomallei Evades Nramp1 (Slc11a1)- and NADPH Oxidase-Mediated Killing in Macrophages and Exhibits Nramp1-Dependent Virulence Gene Expression. Front Cell Infect Microbiol 7:350

Showing the most recent 10 out of 11 publications