Burkholderia pseudomallei (Bp) is an antibiotic resistant, Select Agent bacterial pathogen and the causative agent of the disease melioidosis, with endemicity in tropical regions worldwide. Bp is infectious by several routes of entry into a host, with inhalation representing an important route of entry, and furthermore Bp exhibit a strong lung tropism regardless of the route of entry. Respiratory melioidosis is an acute inflammatory disease of the lung, which progresses into a fatal systemic disease involving all major organs. Bp is a facultative intracellular pathogen which employs the Type 3 Secretion System cluster 3 (T3SS3) to mediate vacuolar escape of Bp from phagocytes, allowing for subsequent outgrowth of the bacteria in the host cytoplasm. Importantly, the specific host cells which support the intracellular lifestyle of Bp have not been well characterized. A critical gap in our understanding of Bp pathogenesis is the identification of which host cell types facilitate a replicative niche for Bp. Identification of these host environments will further provide key insights into which host cells mount an inflammatory response against Bp. It is furthermore poorly understood as to whether the ?cytokine storm? mounted as a response to respiratory melioidosis contributes to morbidity, as recent evidence suggests that excessive neutrophil recruitment is associated with reduced host survival. This suggests that immunomodulation of the innate immune response may represent an excellent method of providing novel therapeutics for a disease which has no licensed vaccine, and minimal treatment options due to inherent genome-encoded antibiotic resistance. We provide preliminary data which demonstrate the therapeutic efficacy of inhaled slow-release IL-12 particles to provide full protection against a lethal Bp respiratory challenge Our central hypothesis is that the host innate immune response to lethal respiratory melioidosis is driven by a poorly-controlled intracellular bacterial proliferation, where immunomodulation represents an effective method of combating disease.
In Specific Aim 1 we will identify the replicative niche of Bp in the lung. We hypothesize that spread of Bp to secondary phagocytes is the leading cause of sepsis/death associated with respiratory melioidosis.
In Specific Aim 2 we will determine the contribution of host innate immune cells to inflammation. We hypothesize that the late-arriving myeloid component causes lethality via the inflammatory mediators they produce.
In Specific Aim 3 we will determine the mechanism of microparticulate IL-12 therapeutic efficacy of respiratory melioidosis. Modification of the state of inflammation of respiratory melioidosis may provide effective control of disease by either encouraging early clearance of pathogen through promoting early inflammation, or by improving outcome through modulating late inflammation.
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