Director, Institute for Immunology

Professor, Physiology & Biophysics
School of Medicine

Professor, Ophthalmology
School of Medicine

Innate immunity, bacterial infections, fungal infections, neutrophils, keratitis

2015 - present Director, Institute for Immunology, UCI
2015 Chancellor’s Professor, UC Irvine

1994-2000 Assistant Professor, Departments of Medicine and Ophthalmology, Case Western Reserve
University, Cleveland, OH
2000-2002 Associate Professor, Departments of Medicine and Ophthalmology, Case Western Reserve University, Cleveland, OH
2002-2004 Associate Professor, Center for Global Health & Diseases and Department of Ophthalmology
2004-2014 Professor, Department of Ophthalmology, Case Western Reserve University, Cleveland.
2004-2014 Director of Research, Department of Ophthalmology and Visual Sciences, CWRU
2015 Director of the Institute for Immunology, University of California at Irvine
2015-present Professor, Departments of Ophthalmology, and Physiology and Biophysics, UC Irvine

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? in Pseudomonas aeruginosa and Streptococcus pneumoniae infected corneas (J. Immunology 2010, 2012, 2015). After demonstrating that neutrophil IL-1? secretion is essential for controlling microbial infections in the cornea, we also identified a molecular pathway leading to IL-1??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??secretion, infected neutrophils use the NLRP3 inflammasome, and that this pathway is driven by P. aeruginosa Exotoxin S (Nat Comm 2023). A 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.

1997 Burroughs Wellcome Foundation New Investigator Award
2004 University of Western Australia Raine Foundation Visiting Professorship
2006 - Research to Prevent Blindness Foundation: Senior Investigator Award
2010 Alcon Research Institute award
2011-2015 Page-Reinhart Endowed Professor, Case Western Reserve University

1. Pathogenesis of Pseudomonas aeruginosa corneal infections. We used P. aeruginosa type III secretion mutants generated by Dr. Rietsch to identify their role in a clinically relevant mouse model of corneal infection (keratitis). We also characterized innate immune responses that regulate disease severity and bacterial survival in vitro and in vivo. More recently, we showed that neutrophils infected with ExoS expressing P. aeruginosa activate the NLRP3 rather than the NLRC4 inflammasome.
a. Minns, M., K. Liboro, A. Rietsch, G. R. Dubyak, E. Pearlman. 2023. The NLRP3 inflammasome selectively drives IL-1ß secretion by Pseudomonas aeruginosa infected neutrophils and regulates bacterial killing in vivo. Nature Communications. 14:5832-5846. PMC10511713.
b. Ratitong, B., M. E. Marshall, M. A. Dragan, C. M. Anunciado, S. Abbondante, and E. Pearlman. 2022. Differential roles for IL-1a and IL-1ß in Pseudomonas aeruginosa corneal infection. J. Immunol. 209:1-11. PMC9922050.
c. Vareechon C, Zmina SE, Karmakar M, Pearlman E, Rietsch A. 2017. Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils. Cell Host & Microbe;21:611-618 e615. PMC5478421.
d. Sun, Y., P. Taylor, A. Rietsch and E. Pearlman. 2012. ExoS and ExoT ADP Ribosyltransferase activities mediate Pseudomonas aeruginosa keratitis by promoting neutrophil apoptosis and bacterial survival. J. Immunol. 188(4):1884-95.

2. Mechanisms of IL-1 beta processing and secretion by neutrophils: Using a murine model of Streptococcus pneumoniae keratitis, we showed that IL-1ß plays an essential role in bacterial killing in infected corneas, and that neutrophils were the predominant source of cleaved, bioactive IL-1 beta? which was mediated by pneumolysin as signal 2 activation of the NLRP3 inflammasome. We also found that in contrast to macrophages, neutrophils release bioactive IL-1 beta in the absence of pyroptotic cell death, which we found is dependent on Gasdermin D (GSDMD), and that GSDMD processing and that the mechanism of IL-1 beta release by neutrophils differs from that of macrophages.
a. Karmakar, M., M. Minns, E.N. Greenberg, J. Diaz-Aponte, K. Pestonjamasp, J.L. Johnson, J.K. Rathkey, D.W. Abbott, K. Wang, F. Shao, S.D. Catz, G.R. Dubyak, and E. Pearlman. 2020. N-GSDMD trafficking to neutrophil organelles facilitates IL-1beta release independently of plasma membrane pores and pyroptosis. Nature Communications 11:2212. PMC7200749.
b. Karmakar, M., M. Katsnelson, G.R. Dubyak, and E. Pearlman. (2016) Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1ß secretion in response to ATP. Nature Communications. 15; 7:10555. PMC4756306.
c. Karmakar, M., M. Katsnelson, N.G. Greene, H. A. Malak, Scott Howell, A. G. Hise, A. Camilli, A. Kadioglu, G. R. Dubyak and E. Pearlman. 2015. Pneumolysin induces K+ efflux and NLRP3/Caspase 1 dependent IL-1ß processing by neutrophils. J. Immunol. 194(4):1763-75. PMID: 25609842.

3. Pathogenesis of fungal keratitis: An award from the Alcon Research Institute in 2010 allowed us to travel to southern India to examine the host response in patients with corneal ulcers caused by pathogenic Fusarium and Aspergillus. We examined corneal ulcer material, post- transplant corneas, and peripheral blood from patients in India (J. Infect Dis 2011, 2015. Clinical studies pointed to a role for neutrophils, which are the predominant infiltrating cells, and provided the basis for development of our murine models of fungal keratitis. In addition to examining the host response to pathogenic Aspergillus and Fusarium species, we identified fungal antioxidant and iron binding pathways as novel therapeutic approaches for fungal keratitis (J. Clin Invest 2012; PLoS Path 2013). Similarly, we showed that neutrophils use calprotectin (S100A8/A9) to sequester zinc and manganese to limit hyphal growth in the cornea (J. Immunol. 2016), and that topical application of the Zn++ inhibitor atovaquone prevents hyphal growth in the cornea by the same mechanism (IOVS 2018). More recently, we identified a requirement for IL-1ß in fungal keratitis and found an unexpected role for caspase-11 in processing by neutrophils. We also showed that neutrophil secretion of IL-1 beta differs from IL-1ß in being mediated by exosomes.
a. Ratitong, B., M. Marshall, E. Pearlman. 2021. ß-glucan stimulated neutrophil secretion of IL-1a is independent of GSDMD and mediated through extracellular vesicles. Cell Reports. 35;109139. PMC8186457.
b. Carrion Sde, J., S. Abbondante, H. Clark, and E. Pearlman. 2019. Aspergillus fumigatus corneal infection is regulated by chitin synthases and by neutrophil–derived acidic mammalian chitinase Eur J Immunol. 10.1002/eji.201847851. PMC6999821.
c. Sun, Y., S. Abbondante, M. Karmakar, S. de Jesus Carrion, C. Che, A. G. Hise and E. Pearlman. 2018. Neutrophil caspase-11 is required for cleavage of caspase-1 and secretion of IL-1ß in Aspergillus fumigatus infection. Journal of Immunology. 201(9):2767-2775. PMC6200591 (Featured in In this Issue as top 10% of papers).
d. Clark, H. L., S. Abbondante, M. S. Minns, E. N. Greenberg, Y. Sun, and E. Pearlman. 2018. Protein Deiminase 4 and CR3 Regulate Aspergillus fumigatus and beta-Glucan-Induced Neutrophil Extracellular Trap Formation, but Hyphal Killing Is Dependent Only on CR3. Front Immunol 9: 1182. PMC5986955.

R01 EY14362-20 (Pearlman, PI) Pathogenesis of Bacterial Keratitis. Currently: 05/21/24-05/20/28.

Pathogenesis of Fungal Keratitis. 03/01/08 – 12/31/23

Society for Leukocyte Biology

Cellular and Molecular Biosciences

Institute for Immunology

Link to this profile
https://faculty.uci.edu/profile/?facultyId=6124

Last updated
06/15/2024