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.
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.)
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
Immunology; Infectious Diseases; Microbial Ecology; Respiratory Disease/Infections; Viruses