Ellen F Foxman, MD, PhD
Research & Publications
Biography
News
Research Summary
Background and research summary. Both seasonal respiratory viruses and emerging viruses such as SARS-CoV-2 have a huge impact on human health and productivity. Even before the current pandemic, respiratory viruses were estimated to cause 500,000M illnesses and contribute to 2M hospitalizations in the U.S. every year. While vaccines and antivirals are effective against some respiratory viruses, not every virus can be targeted with these strategies; furthermore, the great diversity of respiratory viruses and their rapid evolution makes it impossible to target all viruses. Therefore, in order to find effective ways to prevent respiratory virus illnesses, more approaches are needed. Our research goals are (1) to identify natural defense mechanisms the body uses to block replication of respiratory viruses, (2) to understand how environmental exposures influence airway defenses and thereby impact the outcome of respiratory virus infections, and (3) to develop new diagnostic tests for respiratory pathogens based on the host response to infection.
Research Opportunities. Currently there are opportunities for trainees to participate in both basic science and translational research projects. Basic science projects focus on identifying cellular and molecular mechanisms of antiviral defense that alter the course of human respiratory virus infections. Translational research focuses on development of diagnostic tests to categorize airway infections. Experimental approaches include primary cell culture and virology, and transcriptomic, proteomic, and epigenetic analyses of human primary cells and clinical samples.
Extensive Research Description
Background. Over the past decade, the improved technologies for detecting respiratory viruses have revealed that respiratory virus infections are much more frequent than previously appreciated, and that the same viral infection can have a range of outcomes ranging from asymptomatic to serious lung disease. To understand the molecular mechanisms that govern susceptibility to respiratory viruses, study the cell-intrinsic innate immune defenses of the target cells in which these viruses replicate, the epithelial cells that from the lining of the airway.
Impact of recent exposures on antiviral defense.
Viral interference. Respiratory viruses spread through the population in epidemic waves every year, but the forces shaping the timing of these epidemics are not completely understood. Recently, we showed that infection with rhinovirus, the common cold virus, can provide temporary protection against infection with influenza A virus by activating broad antiviral defenses (the interferon response) within airway epithelial cells (Wu and Mihalyova et al, The Lancet Microbe, 2020). This observation fits with epidemiological data showing staggered seasonal epidemics of rhinovirus and influenza A every year, and the observation that the annual autumn rhinovirus season appeared to delay the swine flu epidemic in Europe in 2009.
Oxidative stress. A broad theme emerging from our studies of epithelial innate immune mechanisms is that environmental factors which impact epithelial cell biology can modulate antiviral defenses and alter the course of infection. In several studies, we have observed an impact of certain environmental exposures on defense against rhinovirus, the most frequent cause of the common cold and the #1 trigger of childhood asthma attacks. In recent work, we found that recognition of cytoplasmic viral RNA within airway epithelial cells triggers both the expected antiviral interferon response and a defense response against oxidative stress mediated by the transcription factor NRF2. Further investigation showed that increasing NRF2 activation dampened antiviral signaling, indicating a tradeoff between these two defense responses. We also observed differences in calibration of these protective responses in epithelial stem cells from different regions of the airway (nasal vs. lung). This work indicates that the airway epithelium can adapt and survive when encountering oxidative airway damage, this leaves the epithelium more vulnerable to rhinovirus infection. (Mihaylova et al, Cell Reports, 2018).
Cool temperature. This theme also fits with discoveries from my post-doctoral fellowship, in which our team showed that cool temperature can alter the ability of the airway cells to mount an effective innate immune response against rhinovirus. We discovered that mechanisms used by the innate immune system to protect cells against this virus are quite effective at core body temperature (37°C), but are diminished at slightly cooler temperatures, such as temperatures that might be found in the nasal passages upon inhaling cool ambient air (33°C). (Foxman et al, PNAS, 2015 and Foxman et al, PNAS, 2016). The temperature-dependent signals identified in this study are important in immune defense against many viruses, and these findings suggest that cool areas of the body may provide a niche for certain viruses to evade antiviral defenses.
Studying host response viral infection in vivo in humans. Informed by my experiences as a clinical pathologist, my laboratory has also initiated projects to study host responses to airway infections using clinical samples. In a collaborative project, we recently found that measuring mRNAs and proteins induced by the local airway antiviral interferon response can accurately identify patients with respiratory virus infection using nasopharyngeal swabs (Landry and Foxman, Journal of Infectious Diseases, 2018.)
Coauthors
Research Interests
Asthma; Bacterial Infections; Biology; Common Cold; Cell Biology; Diagnostic Techniques, Respiratory System; Environmental Health; Epithelial Cells; Histology; Immune System; Immunity, Innate; Interferons; Microbiology; Pathology; Respiratory System; Rhinovirus; RNA Virus Infections; RNA Viruses; Viruses, Unclassified; Virology; Immunity, Mucosal; Respiratory Mucosa; Genomics; Infectious Disease Medicine; Translational Research, Biomedical; Epigenomics; Transcriptome
Public Health Interests
Immunology; Infectious Diseases; Microbial Ecology; Respiratory Disease/Infections; Viruses
Research Image
Image for Iwasaki lab website common cold virus project page
Selected Publications
- PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infectionXu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection Nature 2023, 1-9. PMID: 37438530, DOI: 10.1038/s41586-023-06322-y.
- Respiratory viruses: New frontiers—a Keystone Symposia reportCable J, Sun J, Cheon I, Vaughan A, Castro I, Stein S, López C, Gostic K, Openshaw P, Ellebedy A, Wack A, Hutchinson E, Thomas M, Langlois R, Lingwood D, Baker S, Folkins M, Foxman E, Ward A, Schwemmle M, Russell A, Chiu C, Ganti K, Subbarao K, Sheahan T, Penaloza‐MacMaster P, Eddens T. Respiratory viruses: New frontiers—a Keystone Symposia report Annals Of The New York Academy Of Sciences 2023, 1522: 60-73. PMID: 36722473, DOI: 10.1111/nyas.14958.
- Nasal host response-based screening for undiagnosed respiratory viruses: a pathogen surveillance and detection studyCheemarla N, Hanron A, Fauver J, Bishai J, Watkins T, Brito A, Zhao D, Alpert T, Vogels C, Ko A, Schulz W, Landry M, Grubaugh N, van Dijk D, Foxman E. Nasal host response-based screening for undiagnosed respiratory viruses: a pathogen surveillance and detection study The Lancet Microbe 2023, 4: e38-e46. PMID: 36586415, PMCID: PMC9835789, DOI: 10.1016/s2666-5247(22)00296-8.
- Complement Plays a Critical Role in Inflammation-Induced Immunoprophylaxis Failure in MiceEscamilla-Rivera V, Santhanakrishnan M, Liu J, Gibb DR, Forsmo JE, Foxman EF, Eisenbarth SC, Luckey CJ, Zimring JC, Hudson KE, Stowell SR, Hendrickson JE. Complement Plays a Critical Role in Inflammation-Induced Immunoprophylaxis Failure in Mice Frontiers In Immunology 2021, 12: 704072. PMID: 34249009, PMCID: PMC8270673, DOI: 10.3389/fimmu.2021.704072.
- Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kineticsCheemarla NR, Watkins TA, Mihaylova VT, Wang B, Zhao D, Wang G, Landry ML, Foxman EF. Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics Journal Of Experimental Medicine 2021, 218: e20210583. PMID: 34128960, PMCID: PMC8210587, DOI: 10.1084/jem.20210583.
- Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changesRavindra NG, Alfajaro MM, Gasque V, Huston NC, Wan H, Szigeti-Buck K, Yasumoto Y, Greaney AM, Habet V, Chow RD, Chen JS, Wei J, Filler RB, Wang B, Wang G, Niklason LE, Montgomery RR, Eisenbarth SC, Chen S, Williams A, Iwasaki A, Horvath TL, Foxman EF, Pierce RW, Pyle AM, van Dijk D, Wilen CB. Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes PLOS Biology 2021, 19: e3001143. PMID: 33730024, PMCID: PMC8007021, DOI: 10.1371/journal.pbio.3001143.
- Magnitude and timing of the antiviral response determine SARS-CoV-2 replication early in infection.Cheemarla NR, Watkins TA, Mihaylova VT, Wang B, Zhao D, Wang G, Landry ML, Foxman EF. Magnitude and timing of the antiviral response determine SARS-CoV-2 replication early in infection. MedRxiv : The Preprint Server For Health Sciences 2021 PMID: 33532783, PMCID: PMC7852233, DOI: 10.1101/2021.01.22.21249812.
- Viral interference cannot be concluded from datasets containing only symptomatic patients – Authors' replyWu A, Mihaylova VT, Landry ML, Foxman EF. Viral interference cannot be concluded from datasets containing only symptomatic patients – Authors' reply The Lancet Microbe 2021, 2: e10. PMID: 35544223, DOI: 10.1016/s2666-5247(20)30218-4.
- An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and diseaseD’Mello A, Riegler AN, Martínez E, Beno SM, Ricketts TD, Foxman EF, Orihuela CJ, Tettelin H. An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and disease Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 33507-33518. PMID: 33318198, PMCID: PMC7777036, DOI: 10.1073/pnas.2010428117.
- Interference between rhinovirus and influenza A virus: a clinical data analysis and experimental infection studyWu A, Mihaylova VT, Landry ML, Foxman EF. Interference between rhinovirus and influenza A virus: a clinical data analysis and experimental infection study The Lancet Microbe 2020, 1: e254-e262. PMID: 33103132, PMCID: PMC7580833, DOI: 10.1016/s2666-5247(20)30114-2.
- Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium.Ravindra NG, Alfajaro MM, Gasque V, Habet V, Wei J, Filler RB, Huston NC, Wan H, Szigeti-Buck K, Wang B, Wang G, Montgomery RR, Eisenbarth SC, Williams A, Pyle AM, Iwasaki A, Horvath TL, Foxman EF, Pierce RW, van Dijk D, Wilen CB. Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium. BioRxiv : The Preprint Server For Biology 2020 PMID: 32511382, PMCID: PMC7263511, DOI: 10.1101/2020.05.06.081695.
- Analytical sensitivity and efficiency comparisons of SARS-CoV-2 RT–qPCR primer–probe setsVogels CBF, Brito AF, Wyllie AL, Fauver JR, Ott IM, Kalinich CC, Petrone ME, Casanovas-Massana A, Catherine Muenker M, Moore AJ, Klein J, Lu P, Lu-Culligan A, Jiang X, Kim DJ, Kudo E, Mao T, Moriyama M, Oh JE, Park A, Silva J, Song E, Takahashi T, Taura M, Tokuyama M, Venkataraman A, Weizman OE, Wong P, Yang Y, Cheemarla NR, White EB, Lapidus S, Earnest R, Geng B, Vijayakumar P, Odio C, Fournier J, Bermejo S, Farhadian S, Dela Cruz CS, Iwasaki A, Ko AI, Landry ML, Foxman EF, Grubaugh ND. Analytical sensitivity and efficiency comparisons of SARS-CoV-2 RT–qPCR primer–probe sets Nature Microbiology 2020, 5: 1299-1305. PMID: 32651556, PMCID: PMC9241364, DOI: 10.1038/s41564-020-0761-6.
- Experimental Evolution of Human Rhinovirus Strains Adapting to Mouse CellsWasik B, Wasik B, Foxman E, Iwasaki A, Turner P. Experimental Evolution of Human Rhinovirus Strains Adapting to Mouse Cells 2020, 145-157. DOI: 10.1007/978-3-030-39831-6_12.
- Host response-based screening to identify undiagnosed cases of COVID-19 and expand testing capacity.Cheemarla NR, Brito AF, Fauver JR, Alpert T, Vogels CBF, Omer SB, Ko A, Grubaugh ND, Landry ML, Foxman EF. Host response-based screening to identify undiagnosed cases of COVID-19 and expand testing capacity. MedRxiv : The Preprint Server For Health Sciences 2020 PMID: 32577694, PMCID: PMC7302303, DOI: 10.1101/2020.06.04.20109306.
- Poly(I:C) causes failure of immunoprophylaxis to red blood cells expressing the KEL glycoprotein in miceEscamilla-Rivera V, Liu J, Gibb DR, Santhanakrishnan M, Liu D, Forsmo JE, Eisenbarth S, Foxman EF, Stowell SR, Luckey CJ, Zimring JC, Hudson KE, Hendrickson J. Poly(I:C) causes failure of immunoprophylaxis to red blood cells expressing the KEL glycoprotein in mice Blood 2020, 135: 1983-1993. PMID: 32266378, PMCID: PMC7256361, DOI: 10.1182/blood.2020005018.
- Coast-to-Coast Spread of SARS-CoV-2 during the Early Epidemic in the United StatesFauver JR, Petrone ME, Hodcroft EB, Shioda K, Ehrlich HY, Watts AG, Vogels CBF, Brito AF, Alpert T, Muyombwe A, Razeq J, Downing R, Cheemarla NR, Wyllie AL, Kalinich CC, Ott IM, Quick J, Loman NJ, Neugebauer KM, Greninger AL, Jerome KR, Roychoudhury P, Xie H, Shrestha L, Huang ML, Pitzer VE, Iwasaki A, Omer SB, Khan K, Bogoch II, Martinello RA, Foxman EF, Landry ML, Neher RA, Ko AI, Grubaugh ND. Coast-to-Coast Spread of SARS-CoV-2 during the Early Epidemic in the United States Cell 2020, 181: 990-996.e5. PMID: 32386545, PMCID: PMC7204677, DOI: 10.1016/j.cell.2020.04.021.
- Coast-to-coast spread of SARS-CoV-2 in the United States revealed by genomic epidemiology.Fauver JR, Petrone ME, Hodcroft EB, Shioda K, Ehrlich HY, Watts AG, Vogels CBF, Brito AF, Alpert T, Muyombwe A, Razeq J, Downing R, Cheemarla NR, Wyllie AL, Kalinich CC, Ott I, Quick J, Loman NJ, Neugebauer KM, Greninger AL, Jerome KR, Roychoundhury P, Xie H, Shrestha L, Huang ML, Pitzer VE, Iwasaki A, Omer SB, Khan K, Bogoch I, Martinello RA, Foxman EF, Landry ML, Neher RA, Ko AI, Grubaugh ND. Coast-to-coast spread of SARS-CoV-2 in the United States revealed by genomic epidemiology. MedRxiv : The Preprint Server For Health Sciences 2020 PMID: 32511630, PMCID: PMC7276058, DOI: 10.1101/2020.03.25.20043828.
- Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against RhinovirusMihaylova VT, Kong Y, Fedorova O, Sharma L, Dela Cruz CS, Pyle AM, Iwasaki A, Foxman EF. Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus Cell Reports 2018, 24: 3000-3007.e3. PMID: 30208323, PMCID: PMC6190718, DOI: 10.1016/j.celrep.2018.08.033.
- Antiviral Response in the Nasopharynx Identifies Patients With Respiratory Virus InfectionLandry ML, Foxman EF. Antiviral Response in the Nasopharynx Identifies Patients With Respiratory Virus Infection The Journal Of Infectious Diseases 2017, 217: 897-905. PMID: 29281100, PMCID: PMC5853594, DOI: 10.1093/infdis/jix648.
- Early local immune defences in the respiratory tractIwasaki A, Foxman EF, Molony RD. Early local immune defences in the respiratory tract Nature Reviews Immunology 2016, 17: 7-20. PMID: 27890913, PMCID: PMC5480291, DOI: 10.1038/nri.2016.117.
- Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperatureFoxman EF, Storer JA, Vanaja K, Levchenko A, Iwasaki A. Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 8496-8501. PMID: 27402752, PMCID: PMC4968739, DOI: 10.1073/pnas.1601942113.
- Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cellsFoxman EF, Storer JA, Fitzgerald ME, Wasik BR, Hou L, Zhao H, Turner PE, Pyle AM, Iwasaki A. Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 827-832. PMID: 25561542, PMCID: PMC4311828, DOI: 10.1073/pnas.1411030112.
- Genome–virome interactions: examining the role of common viral infections in complex diseaseFoxman EF, Iwasaki A. Genome–virome interactions: examining the role of common viral infections in complex disease Nature Reviews Microbiology 2011, 9: 254-264. PMID: 21407242, PMCID: PMC3678363, DOI: 10.1038/nrmicro2541.
- Use of the Fetal Fibronectin Test in Decisions to Admit to Hospital for Preterm LaborFoxman EF, Jarolim P. Use of the Fetal Fibronectin Test in Decisions to Admit to Hospital for Preterm Labor Clinical Chemistry 2004, 50: 663-665. PMID: 14981040, DOI: 10.1373/clinchem.2003.028720.
- Cover Illustration: Histoplasma capsulatumFoxman EF. Cover Illustration: Histoplasma capsulatum, July 2004-June 2005. Journal of clinical microbiology. 2004; 42.
- Inflammatory Mediators in Uveitis: Differential Induction of Cytokines and Chemokines in Th1- Versus Th2-Mediated Ocular InflammationFoxman EF, Zhang M, Hurst SD, Muchamuel T, Shen D, Wawrousek EF, Chan CC, Gery I. Inflammatory Mediators in Uveitis: Differential Induction of Cytokines and Chemokines in Th1- Versus Th2-Mediated Ocular Inflammation The Journal Of Immunology 2002, 168: 2483-2492. PMID: 11859142, DOI: 10.4049/jimmunol.168.5.2483.
- Integrating Conflicting Chemotactic SignalsFoxman E, Kunkel E, Butcher E. Integrating Conflicting Chemotactic Signals Journal Of Cell Biology 1999, 147: 577-588. PMID: 10545501, PMCID: PMC2151176, DOI: 10.1083/jcb.147.3.577.
- Chemotaxis Assays for Eukaryotic CellsZigmond S, Foxman E, Segall J. Chemotaxis Assays for Eukaryotic Cells Current Protocols In Cell Biology 1998, 00: 12.1.1-12.1.29. PMID: 18228315, DOI: 10.1002/0471143030.cb1201s00.
- Multistep Navigation and the Combinatorial Control of Leukocyte ChemotaxisFoxman E, Campbell J, Butcher E. Multistep Navigation and the Combinatorial Control of Leukocyte Chemotaxis Journal Of Cell Biology 1997, 139: 1349-1360. PMID: 9382879, PMCID: PMC2140208, DOI: 10.1083/jcb.139.5.1349.
- Chemoattractant receptor cross talk as a regulatory mechanism in leukocyte adhesion and migrationCampbell J, Foxman E, Butcher E. Chemoattractant receptor cross talk as a regulatory mechanism in leukocyte adhesion and migration European Journal Of Immunology 1997, 27: 2571-2578. PMID: 9368612, DOI: 10.1002/eji.1830271016.
- Components required for cytokinesis are important for bud site selection in yeast.Flescher EG, Madden K, Snyder M. Components required for cytokinesis are important for bud site selection in yeast. The Journal Of Cell Biology 1993, 122: 373-86. PMID: 8320260, PMCID: PMC2119637, DOI: 10.1083/jcb.122.2.373.