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Given the continuing global burden of infectious disease, the study of host-pathogen interactions is essential for improved therapies that impact human health. We focus on understanding the role of host epigenetic programs that drive innate immune responses to pathogens, how these programs are dysregulated in disease and we how we can harness these mechanisms to boost or subdue immune responses.
The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our bodies first line of defense against infection. These cell-lineage and signal-specific gene expression programs are primarily governed by epigenetic enzymes that regulate posttranslational modifications on histones. This 'histone code’ not only controls the accessibility of the genes to transcription factors, but also serve as docking sites for epigenetic “reader” enzymes that recruit essential transcriptional machinery. Dysregulation of these epigenetic modifiers is a recurrent and sentinel event in malignancy and inflammation. Hence, enzymes that “write”, “erase” and “read” the histone code are the most promising and intently pursued targets in drug discovery today.
While much of the histone code is set during cellular differentiation, pathogens and other environmental triggers also induce changes in the epigenetic landscape that govern gene expression programs in mature immune cells. This raises a very fundamental question of how our environment may influence immune cell behavior and gene expression in the short and long term.
My lab currently has two active areas research: 1) Understanding the role of bromodomain-containing family of epigenetic “readers” for gene expression programs following pathogen infection of innate immune cells and 2) the contribution of small non-coding RNAs and their associated proteins to antiviral immunity.
Dr Kate L. Jeffrey is an Assistant Professor of Medicine at Harvard Medical School, an Assistant in Immunology at Massachusetts General Hospital and an associated researcher at the Broad Institute of MIT & Harvard. Kate performed her undergraduate studies at the University of Melbourne, Australia, and completed her PhD with Professor Charles Mackay at the Garvan Institute of Medical Research in Sydney, Australia. She then worked as an Immunology editor with Nature Medicine in New York in 2007 before performing her postdoctoral research with Professor Sasha Tarakhovsky at The Rockefeller University in New York. Kate is also co-founder of the New York Imagine Science Film Festival, now in its 7th year in New York City. She started her independent laboratory at MGH in 2012.
Dr. Kate Jeffrey
Thier 3 WEL-340
Massachusetts General Hospital
60 Blossom St, Boston, MA 02114
- Postdoc: Stuti Mehta, PhD (University of Oxford, UK)
- Research Technician: Alex Cronkite, BA (Tufts University)
- Research Technician: Tahnee Saunders BSc, M.Biotech (University of Melbourne, Australia)
- Megha Basavappa (currently in PhD program, U Penn Immunology)
- Tim Prior (currently in MD/PhD program, Tulane University)
1) We have previously shown that prevention of acetylated histone "reading" by the bromodomain and extra terminal (BET) family with a specific inhibitor markedly reduced inflammatory gene expression and inflammatory responses in vivo. There are however 46 bromodomain-containing proteins in the human genome and while the therapeutic tractability of this protein family is becoming clear, the biological characterization of these proteins, particularly in immune responses, is lacking. We are currently investigating the roles of novel bromodomain proteins in innate immunity.
2) Plants, insects and C.elegans all use non-coding RNA and RNA interference (RNAi) for silencing viral RNA. The key RNAi effector proteins, Dicer and AGO1-4, are functional in mammalian cells and execute RNAi as well as micro (mi)RNA responses for endogenous gene silencing. Whether mammalian cells still use RNAi/miRNA devices for antiviral defense remains a largely unanswered question of innate immunity. It is thought that pattern recognition receptors (PRR)s leading to the production of antiviral cytokines such as type I interferon have made RNAi mechanisms for antiviral immunity redundant. Using knockout mice and RNA sequencing technologies we are unraveling the contribution of this system to mammalian antiviral immunity.
- Mehta S, Cronkite DA, Basavappa M, Saunders TL, Adiliaghdam F, Amatullah H, Morrison SA, Pagan JD, Anthony RM, Tonnerre P, Lauer GM, Lee JC, Digumarthi S, Pantano L, Sui SJH, Ji F, Sadreyev R, Zhou C, Mullen AC, Kumar V, Li Y, Wijmenga C, Xavier RJ, Means TK, Jeffrey KL. Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140. Sci Immunol. 2017;2(9). DOI: 10.1126/sciimmunol.aag3160.
- Li Y, Basavappa M, Lu J, Dong S, Cronkite DA, Prior JT, Reinecker HC, Hertzog P, Han Y, Li WX, Cheloufi S, Karginov FV, Ding SW, Jeffrey KL. Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells. Nat Microbiol. 2016;2:16250. PMID: 27918527.
- Mehta S, Jeffrey KL. Beyond receptors and signaling: epigenetic factors in the regulation of innate immunity. Immunol Cell Biol. 2015;93(3):233-44. PMID: 25559622.
- Chiang HS, Zhao Y, Song JH, Liu S, Wang N, Terhorst C, Sharpe AH, Basavappa M, Jeffrey KL, Reinecker HC. GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses. Nat Immunol. 2014;15(1):63-71. PMID: 24270516.
- Marazzi I, Ho JS, Kim J, Manicassamy B, Dewell S, Albrecht RA, Seibert CW, Schaefer U, Jeffrey KL, Prinjha RK, Lee K, Garcia-Sastre A, Roeder RG, Tarakhovsky A. Suppression of the antiviral response by an influenza histone mimic. Nature. 2012;483(7390):428-33. PMID: 22419161.
- Nicodeme E*, Jeffrey KL*, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468(7327):1119-23. PMID: 21068722. *Contributed equally. com/7111956
- Cheong C, Matos I, Choi JH, Dandamudi DB, Shrestha E, Longhi MP, Jeffrey KL, Anthony RM, Kluger C, Nchinda G, Koh H, Rodriguez A, Idoyaga J, Pack M, Velinzon K, Park CG, Steinman RM. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell. 2010;143(3):416-29. PMID: 21029863. com/6245956
- Yang JS, Maurin T, Robine N, Rasmussen KD, Jeffrey KL, Chandwani R, Papapetrou EP, Sadelain M, O'Carroll D, Lai EC. Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc Natl Acad Sci U S A. 2010;107(34):15163-8. PMID: 20699384.
- Jeffrey KL, Camps M, Rommel C, Mackay CR. Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov. 2007;6(5):391-403. PMID:17473844.
- Jeffrey K. Rechallenging immunological memory. Nat Med. 2007;13(10):1142. PMID: 17917658.
- Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, Gillieron C, Mackay F, Grey S, Camps M, Rommel C, Gerondakis SD, Mackay CR. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006;7(3):274-83. PMID: 16474395. com/1031133
- Moffatt JD, Jeffrey KL, Cocks TM. Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice. Am J Respir Cell Mol Biol. 2002;26(6):680-4. PMID: 12034566.