Determinants of Outcome and Recurrent Infections in Melioidosis



 DESCRIPTION (provided by applicant): 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.