Allergy and Immunology; Asthma; 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; Infectious Disease Medicine; Translational Medical Research; Epigenomics; Transcriptome
Public Health Interests
Immune functions; Infectious Disease; Infectious Disease Transmission; Microbial Ecology; Respiratory Disease/Infections; Viruses
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
Recently published work has focused on understanding innate immune defense against human rhinovirus. 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. As a research fellow in the Iwasaki laboratory, 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. In two recent studies, our team showed that temperature can alter the ability of the airway cells to mount an effective innate immune response against rhinovirus. By studying airway epithelial cells incubated at different temperatures, 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). Interestingly, we also found that mouse airway epithelial cells and human epithelial cells employed different defense mechanisms to block rhinovirus infection, possibly reflecting co-evolution of the virus with its natural (human) host (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 lower temperature may also provide an opportunity for other viruses that infect the airways or other cool areas of the body to evade antiviral defenses. These findings may also lead to a better understanding of why rhinovirus causes symptoms of disease in the airways of lungs of some individuals, for example people with asthma, but causes only nasal symptoms in other individuals.
Current research directions employ models of the human airway, including primary human cells from different airway regions, 3D airway tissue culture models, and clinical specimens. We are investigating basic mechanisms whereby the body maintains airway health in the setting of frequent exposure to respiratory viruses. Goals include (1) identifying natural defense mechanisms the body uses to block replication of respiratory viruses, focusing on rhinovirus as a model and (2) understanding how the environment influences airway antiviral defense and thereby impacts the outcome of respiratory virus infections. In addition, we are pursuing translational research to developing new diagnostic tests for respiratory infection based on the host response.
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. 2016 DOI: 10.1073/pnas.1601942113
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, and 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. 2015. 112(3):827-32. doi: 10.1073/pnas.1411030112.
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(4):254-64. PubMed PMID: 21407242; PubMed Central PMCID: PMC3678363.
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(3):663-5. PubMed PMID: 14981040.
- Cover Illustration: Histoplasma capsulatum Foxman 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 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(5):2483-92. PubMed PMID: 11859142.
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(3):577-88. PubMed PMID: 10545501; PubMed Central PMCID: PMC2151176.
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(5):1349-60. PubMed PMID: 9382879; PubMed Central PMCID: PMC2140208.
Full List of PubMed Publications
- Iwasaki A, Foxman EF, Molony RD: Early local immune defences in the respiratory tract. Nat Rev Immunol. 2017 Jan; 2016 Nov 28. PMID: 27890913
- 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. Proc Natl Acad Sci U S A. 2016 Jul 26; 2016 Jul 11. PMID: 27402752
- 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. Proc Natl Acad Sci U S A. 2015 Jan 20; 2015 Jan 5. PMID: 25561542
- Foxman EF, Iwasaki A: Genome-virome interactions: examining the role of common viral infections in complex disease. Nat Rev Microbiol. 2011 Apr. PMID: 21407242