Mechanisms of age-related lung inflammation in pulmonary melioidosis - PROJECT SUMMARY Lower respiratory tract infections, including pneumonia, are the most common cause of infection-related death worldwide. Melioidosis is a frequently fatal tropical infection caused by the Tier 1 select agent Burkholderia pseudomallei (Bp). Pulmonary melioidosis manifests in 50% of cases and doubles the risk of death. For the first time, domestically acquired cases of melioidosis were recently reported in the United States, highlighting the emerging nature of this severe infection. Pathogen inhalation is considered the most lethal route of infection, and bacteria aerosolization remains a grave bioterrorism threat. As an intracellular pathogen, Bp replicates in host immune cells, including monocytes, alveolar macrophages, and neutrophils. Activation of the inflammasome, an intracellular sensing protein complex, is therefore thought to be critical to host defense against Bp, leading to IL-1β production as well as pyroptosis. Neutrophil influx to the lung is mediated by monocyte and macrophage-derived IL-1β but can be pathogenic in melioidosis, leading to tissue destruction and ineffective bacterial clearance. Compared to adults, children make up only 5-15% of melioidosis cases and more commonly present with cutaneous infections or abscesses. However, little is known regarding the reasons for these differing characteristics. Using pediatric models of melioidosis, we have found that the juvenile host has resistance to pulmonary melioidosis, highlighted by decreased early neutrophil recruitment and lung IL-1β but increased lung monocytes. We hypothesize that pediatric host resistance to pulmonary melioidosis is dependent on an attenuated early monocyte response leading to reduced pathologic inflammation and improved bacterial clearance. To test these hypotheses, we will leverage in vivo and ex vivo models of pulmonary melioidosis as well as our expertise in innate immunity and pediatric pneumonia to undertake the following specific aims: Aim 1. Determine whether monocyte function impacts age-dependent neutrophilic inflammation in the lung in a murine model of pulmonary infection; Aim 2. Define age-dependent immune responses and the contribution of the inflammasome in a human lung model of pulmonary melioidosis. Completion of these aims will elucidate mechanisms driving resistance to pulmonary melioidosis in the juvenile host. Using age-appropriate models of lung infection, we are positioned to identify new modifiable targets for future treatment strategies.
