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.
Pseudomonas aeruginosa is a common cause of eye infections, particularly in contact lens wearers. If left untreated, these infections can result in rapid loss of vision. The bacterium injects toxic proteins into host immune cells that normally engulf and kill the invading bacteria. Our research is aimed at understanding how these toxic proteins stave off killing by the host immune system, with the hope that a better understanding of their function will lead to the design of targeted therapies to combat or prevent these infections.
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