The purpose of this application is to support the career development of Dr. Ellen Foxman, a board-certified Clinical Pathologist who is currently a research fellow studying host defense mechanisms that block replication of the common cold virus. Dr. Foxman received her M.D. and Ph.D in Immunology from Stanford University and her residency training at Brigham and Women's Hospital. Following a career hiatus for family reasons, Dr. Foxman resumed her career trajectory at Yale, first as post-doctoral associate funded by a re-entry grant and then as a T32 research fellow. The goal of this proposal is to provide Dr. Foxman with additional training and mentored research experience to enable her to develop an independent research program investigating host defense against respiratory viruses. She will achieve this goal through the guidance of her primary mentor and advisory committee, through didactic coursework, and through developing expertise by carrying out the proposed research. Access to outstanding scientific and career development resources at Yale University will support this goal. Dr. Foxman's primary mentor will be Dr. Akiko Iwasaki, an expert in host defense against medically important viruses. The research objective of this proposal is to investigate mechanisms that impact host susceptibility to rhinovirus infection. Rhinovirus is the most frequent cause of the common cold, and has recently been shown to be a major cause of exacerbations of asthma, a disease affecting ~10% of the U.S. population, and a major cause of respiratory distress in young children and patients with chronic lung diseases(1, 9). Experimental infection studies indicate that the virus can amplify greatly in vivo, with as few as 10-100 infectious particles causing disease(2-5). Rhinovirus also can amplify greatly in an epithelial cell monolayer in vitro (~105-fold increase in 48 hr). Interestingly, most rhinoviruses reach higher titers when host cells are incubated at nasal cavity temperature (33-35C) rather than core body temperature (37C)(10). In preliminary studies, Dr. Foxman observed that infection with rhinovirus triggers rapid death of airway epithelial cells corresponding to the end of the replication cycle, but that infected cells live longer if they are incubated at 33C. In this project, Dr. Foxman will investigate the hypothesis that rapid death of host cells limits viral replication, and that cytoprotective responses of host cells prolong each replication cycle, promoting infection. She will test these hypotheses by experimentally modulating cell death pathways in primary human airway cells and through mathematical modeling (in a collaborative team co-mentored by Dr. Andre Levchenko). She will also investigate whether airway epithelial cells undergo cross-protection, a phenomenon well-known in microorganisms(6). In cross-protection, one stressor (i.e. 33C) elicits a cytoprotective stres response that also protects cells from death in response to a distinct stressor (i.e. rhinovirus infection). Human health relevance: These studies will provide insight into mechanisms that govern susceptibility to rhinovirus infection and will help guide future efforts to develop therapeutic interventions for rhinovirus-associated diseases.
Rhinovirus infection is the most frequent cause of the common cold and also a major cause of breathing problems in young children and people with chronic lung diseases, including asthma, a disease affecting ~10% of the U.S. population. In this study, we will investigate the host defense mechanisms that suppress rhinovirus infection within the cells that line the airway. Our results will help us better understand why some people are more susceptible than others to this infection and will guide efforts to develop medicines for preventing or treating rhinovirus infection in the future.
|Mihaylova, Valia T; Kong, Yong; Fedorova, Olga et al. (2018) Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus. Cell Rep 24:3000-3007.e3|
|Iwasaki, Akiko; Foxman, Ellen F; Molony, Ryan D (2017) Early local immune defences in the respiratory tract. Nat Rev Immunol 17:7-20|
|Foxman, Ellen F; Storer, James A; Vanaja, Kiran et al. (2016) 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 113:8496-501|