Profiles

My research program is in immunology and blinding microbial infections of the cornea. This research has been funded by the NIH (National Eye Institute, NEI) for almost 30 years. My first NEI funded project (1993-2008) examined the immune response in a murine model of ocular onchocerciasis (river blindness) where corneas were infected with the filarial nematode Onchocerca volvulus. A major finding from this project was that the inflammatory response was initiated by endosymbiotic Wolbachia bacteria rather than nematode antigens that triggered inflammation (Science 2002). These findings led to NEI supported studies (2003-present) that characterized TLR expression and function in corneal inflammation (J. Biol Chem. 2008, 2013, 2014). This grant also examined the host response, focusing on the role of the pro-inflammatory cytokine IL-1 beta in Pseudomonas aeruginosa and Streptococcus pneumoniae infected corneas (J. Immunology 2010, 2012, 2015). After demonstrating that neutrophil IL-1beta secretion is essential for controlling microbial infections in the cornea, we also identified a molecular pathway leading to IL-1beta secretion by neutrophils that is dependent on P2X7R and on the pore forming protein Gasdermin D (GSDMD); however, in contrast to macrophages, neutrophils do not undergo pyroptotic cell death in part because N-GSDMD does not localize to the neutrophil plasma membrane (Nat Comm 2016, 2020). Our most recent study on P. aeruginosa showed that whereas infected macrophages use the NLRC4 inflammasome to drive IL-1 beta secretion, infected neutrophils use the NLRP3 inflammasome, and that this pathway is driven by P. aeruginosa Exotoxin S (Nat Comm 2023). The NIH R01 grant supporting this work was recently renewed to continue these studies (years 20-24). Our second area of research in lab is on blinding fungal infections of the cornea where we identified Fusarium and Aspergillus virulence factors and neutrophil responses in murine models of this disease. I also worked with collaborators in India to characterize the host response in patients with corneal ulcers. We recently published 2 reviews on fungal infections in the eye that covers some of our findings with patients and using murine models of disease.