Research Departments & Organizations
Asthma; Bacterial Infections; Biology; Cell Biology; Common Cold; Diagnostic Techniques, Respiratory System; Environmental Health; Epigenomics; Epithelial Cells; Genomics; Histology; Immune System; Immunity, Innate; Immunity, Mucosal; Infectious Disease Medicine; Interferons; Microbiology; Pathology; Respiratory Mucosa; Respiratory System; Rhinovirus; RNA Virus Infections; RNA Viruses; Transcriptome; Translational Medical Research; Virology; Viruses, Unclassified
Background and research summary. Respiratory viruses cause one billion colds per year in the U.S. and are also the most common trigger of exacerbations of asthma, a disease affecting about 10% of the population. Respiratory viruses also can cause serious lung infections. However, recent evidence shows that the same viruses that cause these illnesses also frequently enter the airway without causing any symptoms at all. To gain insight into what tips the balance between health and disease during respiratory virus infection, we are studying the antiviral defense mechanisms of airway epithelial cells, the cells that form the lining of the respiratory tract. Overall goals include (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 defense against rhinovirus by airway epithelial cells. Rhinovirus is the virus most commonly found in the nasal cavity, causing about half of common colds and childhood asthma attacks. It is also one of the most frequent asymptomatic viral infections of humans. Translational research focuses on development of new diagnostic tests using patient samples from the Yale New Haven hospital virology laboratory. Experimental approaches include primary cell culture and virology, and transcriptomic, proteomic, and epigenetic analyses of human primary cells and clinical samples.
Extensive Research Description
Understanding susceptibility to respiratory viruses. Rhinovirus is the most frequent cause of the common cold, causes over half of all asthma attacks, and can cause serious lung infections in some patients. However, recent studies show that infection with rhinovirus also frequently results in no symptoms at all. To understand the molecular mechanisms that govern susceptibility to rhinovirus and other respiratory viruses, we are studying cell-intrinsic innate immune defenses of rhinovirus target cells, the epithelial cells that from the lining of the airway.
Tradeoff between oxidative stress and antiviral defense. In recent work, my laboratory investigated a tradeoff in host defense mechanisms that may represent a mechanism linking certain link environmental exposures and to rhinovirus susceptibility. the transcriptional response to viral recognition with airway epithelial cells from different airway regions. 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. 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 and the common cold. In previous work, I studied how rhinovirus infection is affected by an environmental factor widely believed to influence susceptibility to colds: ambient temperature. Since the 1960s, scientists have known that cool temperature promotes rhinovirus replication, but the reason for this was not clear. Our team showed that 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.)
Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus
V.T. Mihaylova, Y. Kong, O. Fedorova, L. Sharma, C. S. Dela Cruz, A. M. Pyle, A. Iwasaki, and E. F. Foxman. ( 2018) Cell Reports. Volume 224, Issue 11. P3000-3007. E3. 2018
Antiviral Response in the Nasopharynx Identifies Patients With Respiratory Virus Infection.
Landry ML, Foxman EF. Antiviral Response in the Nasopharynx Identifies Patients With Respiratory Virus Infection. The Journal Of Infectious Diseases 2018, 217:897-905. 2018
Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature.
Foxman 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, 113:8496-501. 2016
Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells.
Foxman 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, 112:827-32. 2015
Genome-virome interactions: examining the role of common viral infections in complex disease.
Foxman EF, Iwasaki A. Genome-virome interactions: examining the role of common viral infections in complex disease. Nature Reviews. Microbiology 2011, 9:254-64. 2011
Use of the fetal fibronectin test in decisions to admit to hospital for preterm labor.
Foxman EF, Jarolim P. Use of the fetal fibronectin test in decisions to admit to hospital for preterm labor. Clinical Chemistry 2004, 50:663-5. 2004
Cover Illustration: Histoplasma capsulatum
Foxman EF. Cover Illustration: Histoplasma capsulatum, July 2004-June 2005. Journal of clinical microbiology. 2004; 42. 2004
Inflammatory mediators in uveitis: differential induction of cytokines and chemokines in Th1- versus Th2-mediated ocular inflammation.
Foxman 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. Journal Of Immunology (Baltimore, Md. : 1950) 2002, 168:2483-92. 2002
Integrating conflicting chemotactic signals. The role of memory in leukocyte navigation.
Foxman EF, Kunkel EJ, Butcher EC. Integrating conflicting chemotactic signals. The role of memory in leukocyte navigation. The Journal Of Cell Biology 1999, 147:577-88. 1999
Multistep navigation and the combinatorial control of leukocyte chemotaxis.
Foxman EF, Campbell JJ, Butcher EC. Multistep navigation and the combinatorial control of leukocyte chemotaxis. The Journal Of Cell Biology 1997, 139:1349-60. 1997