Iain Fraser, Ph.D.

Iain Fraser, Ph.D.

Credit: NIAID
Chief, Signaling Systems Section

Major Areas of Research

  • Development and application of genome-scale genetic screening to comprehensively define pattern recognition receptor (PRR) response pathways
  • Delineating mechanisms of innate immune signaling and transcriptional control
  • Characterizing combined PRR pathway activation in host-pathogen interactions

Program Description

A recurring theme in human disease is the central influence of inflammation and macrophage activation in numerous pathologies. The macrophage inflammatory response is driven through activation of pattern recognition receptor (PRR) pathways by signals derived from pathogens or tissue damage, and among the PRR families, toll-like receptor (TLR) pathways have been the prototype through their well-studied responses to microbial stimuli. Macrophages constantly evaluate host mucosal surfaces and peripheral tissues for signs of infection or injury. The host must find a balance between tolerance of beneficial microorganisms and minor non-pathological microbial encounter vs. the development of a robust immune response to more serious infections. Emerging evidence suggests that this decision is made by the cell based on the combinatorial signals it receives through PRR engagement by microorganisms and endogenous stimuli.

Our research program is focused on the design, implementation, and interpretation of screening efforts to identify and determine the interactions among the components in PRR signaling networks. We use high-throughput genetic screening to identify key pathway regulators, and a combination of cell biology, biochemistry, and molecular biology to characterize their function. Our goal is to obtain a better understanding of how PRR signaling pathways control the macrophage inflammatory state, and ultimately to develop strategies to regulate these responses in human inflammatory diseases.

Genetic screening to comprehensively characterize immune response pathways

A deeper understanding of how PRR responses are regulated requires unbiased genome-scale screening to broadly characterize the signaling pathways and gene regulatory circuits driving inflammation. The generation of such comprehensive network maps are critical to our collaborative efforts in the LSB to develop fine-grained simulation models of the TLR-driven inflammatory response (Germain et al. Ann. Rev. Immunol. 2011), by providing a more complete set of ‘nodes’ and ‘edges’ for the core biochemical models used as a foundation for such simulations.

We have developed strategies to apply genome-scale genetic screening technologies to interrogate innate immune signaling pathways such as the TLR and inflammasome pathways (Li et al. Sci Rep. 2015). We are employing novel multi-readout signaling and transcriptional reporters to enhance insight from such screens, leading to identification of novel regulators of the macrophage response to bacterial LPS (Li et al. Sci Data. 2017; Sun et al. Sci Data. 2017). We are also developing new integrated bioinformatic approaches to data analysis that are widely applicable and freely available to the research community (Dutta et al. Nat. Commun. 2016). We conduct comparative studies in both mouse and human systems to characterize their similarities and differences, in order to identify the most important targets for potential therapeutic intervention (Sun et al. Sci Signal. 2016). In collaboration with NIH Clinical Center colleagues, we also seek to link novel findings from our screens to cases of human disease.

Mechanisms of innate immune signaling and transcriptional control

The signaling pathways and transcriptional responses induced in macrophages upon TLR stimulation must be tightly controlled to respond appropriately to the pathogenic threat level. These cells must choose when an input meets a ‘danger threshold’ to warrant a robust inflammatory response considering that inappropriate activation can lead to harmful tissue damage. A common theme among hematopoietic cells during an immune response is the activation of NF-kB. This heavily studied transcription factor has provided a classic model for stimulus-dependent transcriptional activation followed by a time-delayed negative feedback loop. We would like to determine how the degree of microbial threat might be decoded in macrophages at the level of NF-kB activity regulation. Furthermore, the mechanisms through which NF-kB activity is integrated with additional PRR-activated transcription factors such as MAPK/AP1 and IRFs is critical to our understanding of macrophage gene regulation.

In this context, we are building on our screening efforts to identify mechanisms of signal integration and transcriptional control that regulate the macrophage inflammatory state. We believe the appropriate homeostatic balance in the macrophage response is achieved through feedback control mechanisms that set cellular response thresholds sensitive to both ligand quantity and complexity (Sung et al. Sci Signal. 2014; Gottschalk et al. Cell Systems. 2016). Combinations of certain microbial signals can also induce ‘non-additive’ synergistic and antagonistic cellular responses, which we seek to dissect using the tools of systems biology (Lin et al. Cell Systems. 2017). Recent evidence from our screens also suggests that innate immune responses are intimately linked to the cellular metabolic state, and this is becoming an emerging aspect of our research program.

PRR signal integration in host-pathogen interactions

Intact microbes present a combination of stimulatory molecules to the cells of our innate immune system. To extend our understanding of how macrophages integrate and respond to complex signals during pathogen encounter, we are developing models of infection with clinically relevant bacterial species (Miller et al. Assay Drug Dev Technol. 2015). We are studying how the combined activation of multiple pathways by invading bacteria, including pathways traditionally considered as antiviral, are integrated to mount an optimal host response to clear a bacterial infection. In parallel, we are also gaining insight to the most critical nodes in the host response pathways by identifying mechanisms used by pathogenic bacteria to evade host defense (Al-Khodor et al. Cell Microbiol. 2014).

The information from this project is critical to understanding how the host response is shaped and influenced by multiple microbe-derived signals, and how this is modified by the presence of additional endogenous stimuli. Such knowledge will have important implications for understanding immunopathologic responses to infection, for design of better vaccines that more accurately mimic the infections that induce robust immunity, and for understanding how some pathogens evade effective immune responses.

Biography

Dr. Fraser received his B.S. in biochemistry from Heriot-Watt University, Edinburgh, Scotland, and his Ph.D. in biochemistry from Imperial College, University of London. He was a Wellcome Trust International postdoctoral fellow at the Vollum Institute in Portland, Oregon. He joined the Alliance for Cellular Signaling (AfCS) research consortium in 2000 as lead scientist of the molecular biology group at the California Institute of Technology and became co-director of the AfCS Molecular Biology Laboratory in 2005. He joined NIAID in 2008 as leader of the PSIIM Molecular and Cell Biology Team, and became chief of the Signaling Systems Unit within the Laboratory of Systems Biology (LSB) in 2011. In 2017 he was appointed as a tenured senior investigator and chief of the Signaling Systems Section.

His research has focused on the mechanistic basis of cellular signaling, both in G protein signaling networks and more recently in toll-like receptor-mediated regulation of inflammatory responses. He applies systems biology approaches to decipher how mammalian cells integrate stimuli in a complex environment to ensure context-dependent cellular responses. This is vital to understanding how a breakdown in information processing through cell-surface receptors and their linked signal transduction pathways leads to human disease.

Special Interest Groups

  • Immunology
  • Systems biology
  • Inflammatory Disease
  • Proteomics
  • Cytokine

Research Group

Sinu John





Sinu John

Sinu John

Credit
NIAID

Sinu John

Credit:
NIAID

Sinu P. John is a Staff Scientist in the Signaling Systems Section. He received his PhD from the University of Alabama at Birmingham and did his post-doctoral work at Harvard Medical School and the Ragon Institute of MGH, Harvard and MIT. His research currently focuses on identifying and understanding the mechanism of genetic and small molecule modulators of macrophage function. Dr. John uses genome-wide approaches and systems biology tools to identify factors that modulate the innate immune response to infectious bacterial and viral stimuli, including SARS CoV-2. Many microbial components and pharmacologically active molecules can induce epigenetic modifications in macrophages imparting long-term ‘training’ of immune responses. Dr. John is interested in identifying such components and molecules with the potential to be developed as therapeutics.  Dr. John is also an adjunct associate professor in the Department of Biochemistry and Molecular & Cellular Biology at Georgetown University and teaches courses in Gene Silencing and Genome Editing and Virology. He also serves on the Review Editorial Board of the MDPI journals; Pathogens, Cells, Viruses and Vaccine.

Jing Sun





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Jing Sun

Credit
NIAID

Jing Sun

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NIAID

Jing Sun is the Ph.D. level Biologist in the Signaling Systems Section. She received her Ph.D./M.D. from Peking University, China, and was trained at Harvard Medical school and NIH before promotion to the Biologist position in 2014. Jing is currently leading multiple projects investigating mechanistic aspects of TLR signaling, with a particular focus on IRAK function and the role of Ubiquitin modification. She also supports the research of other lab members with her advanced technical training in immunology and cell biology. Jing lives in northern Virginia with her beloved family. Reading and hiking are her favorite pastimes.

Clinton Bradfield





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Clinton Bradfield

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NIAID

Clinton Bradfield

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NIAID

Clinton Bradfield is a Research Fellow in the Signaling Systems Section. Originally from Essex, Iowa, he received his BA in Biochemistry from Simpson College where he discovered his interest in molecular biology, organic chemistry, and microbial pathogenesis. Following early exposure to transcriptional analyses (P. Singer), chemical synthesis (T. Nguyen), and viral replication (R. Roller, M. Robek, W. Mothes), he pursued formal MS and PhD training in microbial pathogenesis at Yale University where he studied IFN gamma induced restriction of intracellular bacteria (J. MacMicking). His current projects focus on understanding how intracellular signaling pathways mobilize IL-1 family cytokine release. He has a broad interest in autoinflammatory disorders, microbial pathogenesis, and signal integration. Outside of lab, he enjoys programming, camping, fishing, and spending time with his family.

Rahul Basu





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Rahul Basu

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NIAID

Rahul Basu

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NIAID

Rahul Basu is a postdoctoral fellow under the Rocky Mountain Lab (RML)-Bethesda (Rocky-Beth) collaborative program. He received his PhD from the Indian Institute of Science Education and Research (IISER) Kolkata, India where his project was directed to understand the changes in neuroglial interaction in a murine coronavirus infection model. In 2017, he joined Dr. Karin Peterson’s Neuroimmunology Section at RML to study the age-related changes in blood-brain barrier permeability that contributes to La Crosse virus (bunyavirus) susceptibility in children. Through the Rocky-Beth Program, he transitioned to Dr. Fraser’s Signaling Systems Section in 2019 to perform focused genetic screening and host-factor targeting in his La Crosse study. Since the onset of the COVID pandemic, he has also worked on development of SARS-CoV-2 coronavirus infection models. Outside the lab Rahul loves travelling and landscape photography.

Sam Katz





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Sam Katz

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NIAID

Sam Katz

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NIAID

Sam Katz joined the Signaling Systems Section as a graduate student in the NIH-OxCam program in 2016. He received his PhD from the University of Cambridge in 2020 (co-supervised by Dr. Fraser and Prof. Clare Bryant). As a graduate student, Sam built the SIGNAL platform (signal.niaid.nih.gov) for prioritizing candidates from high-throughput studies. His current focus is on characterizing how post-translation modifications, such as alternative splicing, regulate the inflammatory response. When not thinking about giant gene datasets Sam is most likely cooking from a cuisine that’s new to him or, if he will be presenting at lab meeting that week, baking.

Jonathan Liang





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Jonathan Liang

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NIAID

Jonathan Liang

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NIAID

Jonathan Liang is an MD/PhD student who has recently completed his graduate work through the NIH-OxCam Scholars Program. He is a DC-area native, having lived near NIH since middle school. After undergraduate studies at Yale University in New Haven, CT, he completed a master’s degree at the University of Cambridge before beginning his MD/PhD jointly between the Yale School of Medicine, the NIH, and the University of Cambridge. His research seeks to understand the molecular pathways that allow saturated fatty acids to trigger the NLRP3 inflammasome, an interaction that may contribute to inflammation in diseases such as atherosclerosis and fatty liver disease. His major clinical interest is in pediatrics. Beyond research, Jonathan is an active church member, an enthusiastic cyclist, and a proud nerd who enjoys tabletop role-playing and trading card games.

Julia Gross





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Julia Gross

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NIAID

Julia Gross

Credit:
NIAID

Julia Gross is a graduate student in the NIH GPP/Emory IMP program. She hails from San Francisco CA, studied as an undergrad at Brown University in Providence RI, and currently lives in Washington DC while working on her thesis at NIAID. Her project is centered on understanding how different types of antibiotic treatments impact patients’ immune responses to bacterial infections. More broadly she is interested in research on innate immune signaling writ large as well as anything and everything to do with understanding and combatting the increasing threat of antimicrobial resistant bacteria. Outside the lab Julia can be found performing improv comedy, reading novels, and knitting.

Asmaysinh Gharia





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Asmaysinh Gharia

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NIAID

Asmaysinh Gharia

Credit:
NIAID

Asmaysinh Gharia is a graduate student in the NIH Oxford-Cambridge Scholars program. He grew up in Naperville IL, completed his undergraduate studies at the University of California Berkeley, and is currently conducting the first part of his thesis research in Cambridge in the UK. His project seeks to develop microelectronic and microfluidic devices for efficient production of cellular immunotherapies in collaboration with George Malliaris’ Bioelectronics Lab at the University of Cambridge. In the long run, he is interested in creating technologies to probe cellular dynamics and interactions at a single-cell resolution. In addition to working, Asmaysinh enjoys bouldering, cooking, and travelling.

Makheni Jean Pierre





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Makheni Jean Pierre

Credit
NIAID

Makheni Jean Pierre

Credit:
NIAID

Makheni Jean Pierre is a postbaccalaureate fellow who joined the Signaling Systems Section in 2020 through the Undergraduate Scholarship Program (UGSP). He obtained his associate degree in science from Queensborough Community College (QCC New York) then transferred to Stony Brook University to complete his bachelor’s in biology. His interest lies in the intracellular signaling processes in macrophages in response to activation by pathogens. He is currently working on a target protein discovered in a genetic screen that regulates the expression of key genes involved in the TLR4 pathway in macrophages, in order to control the degree of immune response in certain situations. Outside of lab, he likes to play soccer, cook, travel, bike everywhere, and work out. He gives a lot of importance to his mental health and strives for an optimal work life balance.

Camille Lake





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Camille Lake

Credit
NIAID

Camille Lake

Credit:
NIAID

Camille Lake is a rotating fellow in NIAID’s Emerging Leaders in Data Science Fellowship program. She spent her upbringing in the hills of Northern California, and eventually moved to Santa Barbara where she got her college degree and discovered her love of molecular biology. She moved to Bethesda, MD to pursue her PhD in infectious diseases and immunology at Uniformed Services University of the Health Sciences, where she graduated in 2021. She utilizes her immunology foundation and fascination with data science to fuel her research, which ranges from determining the underpinnings of molecular mimicry in SARS-CoV-2 sequelae to utilizing machine learning algorithms to unlock the secrets of RNA regulation. When not training actively as a mad scientist, she can be found with her nose in a good fantasy novel, playing fetch with her dog Archie, or watching horror movies with her husband Zach.

Selected Publications

Liang JJ, Fraser IDC, Bryant CE. Lipid regulation of NLRP3 inflammasome activity through organelle stress. Trends Immunol. 2021 Sep;42(9):807-823. doi: 10.1016/j.it.2021.07.005. Epub 2021 Jul 30. PMID: 34334306.

Dorrington MG, Bradfield CJ, Lack JB, Lin B, Liang JJ, Starr T, Ernst O, Gross JL, Sun J, Miller AH, Steele-Mortimer O, Fraser IDC. Type I IFNs facilitate innate immune control of the opportunistic bacteria Burkholderia cenocepacia in the macrophage cytosol. PLoS Pathog. 2021 Mar 8;17(3):e1009395. doi: 10.1371/journal.ppat.1009395. Erratum in: PLoS Pathog. 2021 Aug;17(8):e1009821. PMID: 33684179; PMCID: PMC7971856.

Ernst O, Sun J, Lin B, Banoth B, Dorrington MG, Liang J, Schwarz B, Stromberg KA, Katz S, Vayttaden SJ, Bradfield CJ, Slepushkina N, Rice CM, Buehler E, Khillan JS, McVicar DW, Bosio CM, Bryant CE, Sutterwala FS, Martin SE, Lal-Nag M, Fraser IDC. A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation. Sci Signal. 2021 Aug;14(694):eabe0387. doi: 10.1126/scisignal.abe0387. PMID: 34344832.

Katz S, Song J, Webb KP, Lounsbury NW, Bryant CE, Fraser IDC. SIGNAL: A web-based iterative analysis platform integrating pathway and network approaches optimizes hit selection from genome-scale assays. Cell Syst. 2021 Apr;12(4):338-352.e5. doi: 10.1016/j.cels.2021.03.001. Epub 2021 Mar 24. PMID: 33894945.

Dutta B, Azhir A, Merino LH, Guo Y, Revanur S, Madhamshettiwar PB, Germain RN, Smith JA, Simpson KJ, Martin SE, Buehler E, Fraser ID. An interactive web-based application for Comprehensive Analysis of RNAi-screen Data. Nat Commun. 2016 Feb;7:10578. doi: 10.1038/ncomms10578. Erratum in: Nat Commun. 2016;7:11214. Beuhler, Eugen [Corrected to Buehler, Eugen]. PMID: 26902267; PMCID: PMC5477503.

Sun J, Li N, Oh KS, Dutta B, Vayttaden SJ, Lin B, Ebert TS, De Nardo D, Davis J, Bagirzadeh R, Lounsbury NW, Pasare C, Latz E, Hornung V, Fraser ID. Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use. Sci Signal. 2016 Jan;9(409):ra3. doi: 10.1126/scisignal.aab2191. PMID: 26732763; PMCID: PMC5381726.

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