P. aeruginosa type III secreted effectors in corneal disease

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 DESCRIPTION (provided by applicant): P. aeruginosa is one of the most common causes of microbial keratitis, both in the U.S. and worldwide. P. aeruginosa uses a molecular syringe, called type III secretion system, to avoid killing by infiltrating neutrophils, thereby preventing clearance of the infection. P. aeruginosa isolates can be divided into two categories, based on the effector proteins these strains inject using their type III secretion system. "Cytotoxic" isolaes produce ExoU and ExoT, whereas "invasive" isolates produce ExoS and ExoT. We recently discovered that invasive isolates of P. aeruginosa use ExoS and ExoT to inhibit the two major bactericidal functions of neutrophils, reactive oxygen species production and fusion of antimicrobial granules with the bacteria-containing phagosome. Accordingly, the proposed program of research will examine the molecular pathways in neutrophils that ExoS and ExoT inhibit to block reactive oxygen species production (Aim 1) and granule fusion (Aim 2). We will also determine whether injection of ExoS- and ExoT into neutrophils can promote corneal infection on a population level, by inactivating neutrophils through induction of apoptosis, or effector-mediated inhibition of phagocytosis. Here the first phagocytosed bacterium would act as a poison pill, inactivating the neutrophil, thereby allowing the other bacteria to thrive (Aim 3). Our program of research is therefore poised to discover multiple cellular processes that are inhibited by P. aeruginosa, and uncover new approaches to therapeutically intervene in the infection.