Pseudomonas aeruginosa (PA) is one of the two most frequent causes ofhospital-acquired pneumonia (HAP), a disease that afflicts 10% of all patients admittedto intensive care units (170). Studies in humans and animal models have shown that thetype III secretion system of PA plays an important role in the pathogenesis of infectionscaused by this bacterium. This system injects four effector proteins into mammaliancells during infection: ExoU, ExoS, ExoT, and ExoY. Our overall objective has been todefine the contribution of this system and the individual effector proteins secreted by it tothe pathogenesis of acute pneumonia. Our prior studies have demonstrated that secretion of ExoU has the most markedimpact on morbidity and mortality in acute pneumonia, both in humans and animalmodels. Much is known about the molecular and cellular effects of this toxin. Forexample, it is a phospholipase toxin that causes necrosis following injection into manydifferent mammalian cell types in vitro. Despite this wealth of molecular and cellularknowledge, it remains unclear how PA wields this potent weapon to cause overwhelminginfection and death during pneumonia. This proposal will continue our studies utilizing a mouse model to clarify the roleof ExoU in the pathogenesis of acute pneumonia and how ExoU secretion results inespecially severe pneumonia. Our preliminary data show that whereas ExoU- PAbacteria are rapidly cleared from the lungs over the first 24 hr of infection, ExoU+bacteria persist in high numbers. We therefore hypothesize that ExoU is targeted tospecific cell types during the first 24 hr of infection, which in turn compromisespulmonary defenses and allows PA to persist in the lungs rather than be cleared.Our studies will broadly examine which pulmonary cells are targeted for injection ofExoU but will pay special attention to ExoU interactions with phagocytic cells, sincethese cells are rapidly recruited to the lungs during this time period and constitute adefensive barrier that must be overcome by any pathogen if it is to persist in the lungs.Such persistence lays the foundation for subsequent tissue injury and thepathophysiological manifestations of pneumonia. The completion of these aims will define the cellular targets of ExoU and whetherthese phagocytes are killed by ExoU during early acute pneumonia. This information willin turn lay the foundation for future studies designed to block ExoU intoxication, whichmay lead to therapeutic interventions useful in the treatment or prevention of HAP.
|Effective start/end date||8/1/11 → 3/31/14|
- National Institute of Allergy and Infectious Diseases (4R01AI053674-08)