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Principal Investigator: Meghan Elizabeth Rebuli
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $607,668
Funding agency: National Institute of Environmental Health Sciences
PROJECT SUMMARY
Wildfire smoke increasingly contributes to ambient air pollution and more specifically PM2.5 and has been
associated with increased respiratory virus morbidity and mortality. We have previously shown that exposure of
human volunteers to woodsmoke (WS) significantly modifies acute antiviral host defense responses to influenza.
Similarly, we have preliminary evidence indicating that simulation of wildfire smoke affects viral infections in
human nasal epithelial cells (HNECs) in vitro. Since concurrent exposures to wildfires and respiratory viruses
will likely increase worldwide due to climate change, understanding the clinical manifestation, cellular
mechanisms, and chemical components causing modified antiviral defense presents an important research gap
critical to public health. We have already demonstrated that computational modeling approaches can establish
the presence of harmful chemicals in different wildfire smoke conditions as drivers of toxicity. Integrating these
translational research and computational analysis models, the central hypothesis of this proposal is that wildfire
smoke affects multiple steps of antiviral defense pathways in the respiratory mucosa and that chemical
signatures within the complex pollutant mixtures can be associated as drivers of biological responses. Specific
Aim 1 will use in vitro exposure and infection of HNECs to determine the mechanisms of wildfire smoke-induced
changes in antiviral defense function and identify the chemical signatures mediating these responses. HNECs
will be exposed to a variety of different emission mixtures simulating different wildfire scenarios. Changes in viral
infection and multi-omic assessment of immune and inflammatory responses will be assessed. Using
computational modeling, chemical and molecular signatures driving the responses in HNECs in vitro will be
determined. Specific Aim 2 will determine the effects of WS exposures and influenza infection on nasal immunity
in humans in vivo, using inoculation with the live attenuated influenza virus (LAIV) vaccine as a model to elicit
antiviral defense responses in the respiratory mucosa. Volunteers will be randomized for exposures to
WS/Filtered Air followed by inoculation with LAIV/Placebo. Using multi-omic platforms, samples will be analyzed
for immune biomarkers, as well as markers of viral replication and sinonasal symptoms, followed by
computational analysis associating biomarkers with infection outcomes. This application aims to
comprehensively assess the impact of wildfires on respiratory mucosal antiviral defenses by examining viral
entry and replication, antibody production, as well as mucosal metabolomics, transcriptomics, and proteomics
mediating cellular defenses. The parallel investigations of in vitro (SA1) and clinical (SA2) outcomes will yield
both immediate translational impact and in-depth mechanistic insights into the effects of wildfires on respiratory
antiviral defenses. Ultimately, this application will elucidate the mechanisms and chemical signatures through
which wildfire exposures disrupt respiratory innate immune defenses and correlate these changes with
alterations of nasal mucosal host defense functions in humans in vivo.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Ab response><Acute><Address><Affect><Air><Air Pollutants><Airway mucosa><Anti-viral Response><Antibodies><Antibody Formation><Antibody Production><Aromatic Polycyclic Hydrocarbons><Attenuated><Automobile Driving><Biological><Biological Markers><Biomass><Body Tissues><COVID-19 virus><COVID19 virus><Cell Count><Cell Culture Techniques><Cell Number><Chemicals><Chemistry><Clinical><CoV-2><CoV2><Complex><Complex Mixtures><Computer Analysis><Computer Models><Computerized Models><Coupled><Data><Disease Outbreaks><Disease Outcome><Elements><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology><Epidemiology Research><Epithelial Cells><Exposure to><Gene Expression><Genes><Grippe><Health><Host Defense><Human><Human Volunteers><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Markers><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunity><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunologic Markers><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><In Vitro><Infection><Inflammatory Response><Influenza><Influenza Virus><Investigation><Investigators><Knowledge><Link><Liquid substance><Mediating><Mediator><Metals><Modeling><Modern Man><Molecular Fingerprinting><Molecular Profiling><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Nasal><Nasal Epithelium><Nasal Mucosa><Nasal Passages Nose><Nose><Outbreaks><Outcome><PM2.5><Pathway interactions><Pattern><Physical condensation><Placebos><Plastics><Population Growth><Predisposition><Proteins><Proteomics><Public Health><Publishing><Randomized><Research><Research Personnel><Researchers><Respiratory Mucosa><Respiratory System, Nose, Nasal Passages><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Sham Treatment><Site><Smoke><Source><Structure of mucous membrane of nose><Susceptibility><Symptoms><System><Time><Tissues><Toxic effect><Toxicities><Translational Research><Translational Science><Viral><Viral Diseases><Viral Markers><Viral Respiratory Tract Infection><Virus><Virus Diseases><Virus Replication><Wildfire><Wood><Wood material><Wuhan coronavirus><air filter><ambient air pollution><anthropogenesis><anthropogenic><antibody biosynthesis><attenuate><attenuates><bio-markers><biologic><biologic marker><biomarker><biomarker signature><cell culture><cell cultures><climate change><climatic changes><clinical relevance><clinically relevant><computational analyses><computational analysis><computational modeling><computational models><computer analyses><computer based models><computerized modeling><condensation><coronavirus disease 2019 virus><coronavirus disease-19 virus><defense response><driving><epidemiologic><epidemiologic investigation><epidemiological><epidemiology study><experience><exposed human population><extracellular vesicles><fine particles><fine particulate matter><flu infection><flu virus infection><fluid><global climate change><hCoV19><healthy volunteer><host response><human exposure><immune system response><immune-based biomarkers><immunoglobulin biosynthesis><immunological biomarkers><immunological markers><immunoresponse><in vitro Model><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenzavirus><insight><liquid><live attenuated flu vaccine><live attenuated influenza vaccine><live attenuated influenza virus vaccine><metabolism measurement><metabolomics><metabonomics><molecular profile><molecular signature><mortality><multiomics><multiple omics><nCoV2><outdoor air pollution><panomics><pathway><peripheral blood><physiological defense response><pollutant><polyaromatic hydrocarbons><polynuclear aromatic hydrocarbon><predictive biomarkers><predictive marker><predictive molecular biomarker><public health research><randomisation><randomization><randomly assigned><respiratory><respiratory virus><response><sex><sham therapy><simulation><skills><tool><transcriptomics><translation research><translational impact><translational investigation><viral infection><viral multiplication><viral replication><viral respiratory infection><virus infection><virus multiplication><virus-induced disease><volunteer><wild fire><wildland fire><wood smoke><woodsmoke>