Innate immunity, bacterial infections, fungal infections, neutrophils, keratitis
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 Professorship, Case Western Reserve University
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 Professor, Departments of Ophthalmology, and Physiology and Biophysics, UC Irvine
My research program has focused on the innate immune response to parasitic, fungal, and bacterial infections, which has been NIH funded for over 20 years. My earlier studies examined the host response to the parasitic nematode Onchocerca volvulus, which causes ocular onchocerciasis (river blindness), and we reported that endosymbiotic Wolbachia bacteria have a major role in inducing corneal inflammation (Science, 2002). Subsequently, my research program has been examining blinding fungal and bacterial infections of the cornea (keratitis), and is funded by two RO1 grants from the National Eye Institute. These studies examine the role of neutrophils and inflammatory monocytes in immune regulation, microbial killing and in tissue damage. As Director of the Institute for Immunology I run the T32 training grant at UCI that covers 4 pre-doctoral positions per year. I have trained 8 pre-doctoral students and 18 post-doctoral fellows, many of whom have continued in academia.
Pathogenesis of fungal corneal infections Our murine studies on fungal keratitis are based on corneal ulcer material, post- transplant corneas, and peripheral blood from patients in southern India (J. Infect Dis 2015. 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, and thereby limit hyphal growth in the cornea, and that topical application of atovaquone inhibits hyphal growth in the cornea by the same mechanism (IOVS 2018). We also revealed a role for CR3 rather than Dectin-1 in NETosis and hyphal killing in response to fungal pathogens, we reported an unexpected role for caspase-11 in IL-1ß processing by neutrophils, and found a role for acidic mammalian chitinase (AMCase) in fungal keratitis.
1. 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. PMID: 30903663
2. 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)
3. Clark, H.L., S. Abbondante, M.S. Minns, Y. Sun, E. N. Greenberg, and E. Pearlman. 2018. Protein Deiminase 4 (PAD4) and CR3 regulate Aspergillus fumigatus and ?-glucan – induced neutrophil extracellular trap formation, but hyphal killing is dependent only on CR3. Frontiers Immunol. 9:1182. PMC5986955.
4. Clark, H. L., A. Jhingran, Y. Sun, C. Vareechon, S. de Jesus Carrion, E.P. Skaar, W.J. Chazin, J.A. Calera, T.M. Hohl, and E. Pearlman. (2016) Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection. J Immunol 196, 336-44. PMC4684987 (Featured in In this Issue as top 10% of papers)
IL-1 beta processing by neutrophils: Using a murine model of Streptococcus pneumoniae keratitis, we showed that IL-1ß plays an essential role in bacterial clearance, 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 marked contrast to macrophages, neutrophils release bioactive IL-1 beta in the absence of pyroptotic cell death. We recently reported that this process is dependent on Gasdermin D (GSDMD), and that GSDMD processing and that the mechanism of IL-1ß release by neutrophils differs at multiple levels from that of macrophages.
1. 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.
2. 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. 194:1763-75. PMC4369676.
3. Karmakar, M., M. Minns, G. R. Dubyak, E. Pearlman et al. 2020. N-GSDMD trafficking to neutrophil organelles facilitates IL-1ß release independently of plasma membrane pores and pyroptosis. Nature Communications. In press.
Pathogenesis of Pseudomonas aeruginosa corneal infections: EY14362 was first awarded in 2004 with the goal of understanding the role of Toll Like Receptors (TLR) in corneal inflammation. In the first funding period, we characterized TLR signaling in the corneal epithelial cells and in infiltrating macrophages and neutrophils, resulting in multiple papers in the Journal of Biological Chemistry, J. Immunol, J. Leukocyte Biology, and IOVS. Subsequent studies with Arne Rietsch at CWRU characterized TLR signaling in Pseudomonas aeruginosa keratitis, which we reported in 2010 in J Immunol (PMC3392180). We also identified the ADPRT region of ExoS and ExoT as the essential P. aeruginosa type III secretion (T3SS) virulence factors in keratitis (J. Immunol 2012. PMC3273577). We continued this collaboration after I moved to UCI, demonstrating that ExoS enhances P. aeruginosa survival in human neutrophils by inhibiting ROS production by ADP ribosylating Ras and thereby blocking NADPH oxidase assembly (Cell Host and Microbe 2017).
Our studies in India showed that IL-1 beta gene expression was elevated in human corneal ulcers caused by bacteria, which were mostly comprised of neutrophils (PLoS One 2013, PMC3672173). Using a murine model of P. aeruginosa keratitis, we showed that IL-1ß plays an essential role in bacterial clearance, and that neutrophils were the predominant source of cleaved, bioactive IL-1 beta
1. Vareechon C, S.E. Zmina, M. Karmakar, E. Pearlman, and A. Rietsch. (2017) Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils. Cell Host & Microbe 21: 611-618 e615. PMC5478421.
2. Karmakar, M., Y. Sun, A. G. Hise, A. Rietsch and E. Pearlman. 2012. Cutting Edge: IL-1ß processing during Pseudomonas aeruginosa infection is mediated by neutrophil serine proteases and is independent of NLRC4 and Caspase-1. J. Immunol. 189:4231-4235. PMC3482477
3. 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. PMC3273577.
4. Sun, Y. M. Karmakar, S. Roy, R. T. Ramadan, S. R. Williams, S. Howell, C. L. Shive, Y. Han, C. M. Stopford, A. Rietsch and E. Pearlman. 2010. TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. J. Immunol. 185:4272-83. PMC3392180.
National Eye Institute
Pathogenesis of Fungal Keratitis
Proposed studies will examine the role of IL-1 alpha and osteopontin in human neutrophils and in murine models of fungal keratitis. Studies will also characterize the role of neutrophil extracellular traps (NETs), which can limit hyphal growth, but also have the potential to contribute to tissue damage.
Role: PI (30% effort)
Annual direct costs: $271,517
RO1 EY014362 Pearlman (co-PI) 12/01/03 – 8/30/23
National Eye Institute
Pathogenesis of Bacterial Keratitis
This project examines the role of IL-1 beta and inflammasomes in the innate immune response in bacterial keratitis and in response to bacterial products in the cornea
Role: Co-PI (10% effort) with George Dubyak, CWRU
Annual direct costs: $260,000
NIAID R21 AI149239 Pearlman (co-PI) 7/01/20 – 6/30/22
Epigenetic regulation of the IL-17 promoter landscape in neutrophils
This project will examine epigenetic regulation of IL-17 and related genes by human and murine neutrophils using ATAC sequencing and ChIP sequencing approaches.
Role: PI (5% effort)
Annual Direct costs: $150,000
NIAID T32 AI060573 Pearlman (PI) 08/18/16 – 07/31/21
Immunology Research Training Grant for UC Irvine
This grant covers the tuition and stipends for 3 pre-doctoral positions (a 4th position is provided by UCI School of Graduate Studies).
Role: PI (5% effort)
Annual direct costs: $110,550
R01 EY030150 (Li-Jun Ma, UMASS, PI) 05/01/19 – 04/30/2024
Identify novel Fusarium virulence factors
This grant will use comparative genomics studies pathogenic F. oxysporum clinical isolates to identify novel virulence factors. The approach will use a high -throughput screening pipeline in the Ma lab, including transcriptomics, forward/reverse genetics and experimental evolution approaches to identify potential virulence factors that will be tested in murine models of fungal keratitis in the Pearlman lab.
Role: Co-Investigator (5% effort)
Pathogenesis of Fungal Keratitis. 03/01/08 – 12/31/23
Cellular and Molecular Biosciences
Cellular and Molecular Biosciences