Theses and Dissertations from UMD
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Item BIOMATERIAL BASED STRATEGIES FOR VIRAL AEROSOL CAPTURE AND PREVENTION OF RESPIRATORY INFECTIONS(2024) Doski, Shadin; Duncan, Gregg; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In the 2022-2023 flu season, the Center for Disease Control (CDC) estimated 21,000 deaths and 31 million symptomatic illnesses in the United States. Current FDA approved antivirals for influenza are grouped into three categories, matrix protein 2 (M2) inhibitors, neuraminidase inhibitors (NAI) and polymerase acidic protein cap-dependent endonuclease (CEN) inhibitors. However, limitations of these treatments have been evident. For example, NAI inhibitors require early treatment to be efficacious and some influenza strains can develop resistance to both NAI and CEN inhibitors. Thus, there is a need for new classes of antivirals as well as better understanding of influenza transmission and monitoring of influenza to inform development of efficacious interventions. In chapter 2 we describe how we design biomaterials inspired by the physiological characteristics of mucus to capture and trap pathogens. We performed studies to establish this material as a suitable substrate for viral capture and release after collection using advanced aerosol capture technology. In chapter 3, we formulate an antiviral based around polyinosinic polycytidylylic acid (polyIC). PolyIC is commonly used in research as an adjuvant in vaccine delivery through its targeting of Toll like receptor 3 (TLR3). This pathway also results in type 1 and 3 interferon production, which in turn stimulate a range of antiviral mechanisms. Because of this, it has also been investigated as a prophylactic or treatment to various viruses, including hepatitis B virus, human immunodeficiency virus and rhinovirus. However, due to stability and toxicity concerns, it has not been implemented as an inhaled treatment to induce local immunity in the lungs at the site of infection. Towards this end, we used polyethylene imine-polyethylene glycol (PEI-PEG) copolymer to condense PolyIC into nanoparticles to enhance their bioavailability in target cells. By combining the two, we can utilize the antiviral capabilities of Poly(IC) while minimizing the dosage concentration to therapeutic levels.Item EXHALED BREATH AEROSOL TRANSMISSION OF ACUTE RESPIRATORY INFECTIONS(2023) Lai, Jianyu; Milton, Donald K; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Acute respiratory infections (ARIs), which usually appear in the form of common colds and influenza, as well as outbreak brought on by emerging viruses such as SARS-CoV-2, result in millions of deaths and hospitalizations each year. Aerosols being exhaled by infected population and inhaled by susceptible population has been identified as an important transmission route for ARIs; yet few studies have compared the viral load in exhaled breath aerosol (EBA) in naturally and experimentally infected cases, as well as among various infections. The specific aims of this dissertation were: 1) examine the comparability of EBA viral shedding between experimentally and a full range of natural ambulatory influenza cases; 2) compare seasonal coronavirus, influenza, SARS-CoV-2 Omicron, and other SARS-CoV-2 variants in terms of viral loads in exhaled breath aerosols; and 3) examine the relative efficacy of face masks, KN95, and N95 respirators as source control for SARS-CoV-2. We analyzed data from four studies that collected 30-minute fine (≤5 μm) and coarse (>5 μm) EBA samples using a Gesundheit-II sampler. Viral RNA load in EBA was quantified using real-time RT-PCR. Nasal inoculation of influenza virus A/Wisconsin/67/2005 showed lower EBA viral shedding compared to the natural influenza A H3 infections. Among the viruses studied, SARS-CoV-2 Omicron variants demonstrated the highest viral RNA loads in both EBA size fractions, emphasizing its superior spread capability via inhalation. Furthermore, while all masks and respirators showed significant reductions in viral RNA load in exhaled aerosols, the duckbill N95 respirators stood out, providing reductions of up to 99% and outperforming both surgical and cloth masks, and KN95 respirators. Given the evident transmission risk via inhalation for the studied viruses, measures such as masking and indoor air hygiene are crucial. The pronounced efficacy of N95 respirators highlights their importance in healthcare settings and places with vulnerable populations, especially during periods of heightened respiratory viral infections.Item MUCIN-MEDIATED AND INTERFERON-DRIVEN DEFENSE MECHANISMS AGAINST INFLUENZA VIRUS INFECTION IN HUMAN AIRWAY EPITHELIUM(2022) Iverson, Ethan; Scull, Margaret A; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The human airway epithelium represents the primary site of infection for many respiratory viruses, including influenza A virus (IAV). To safeguard this tissue and maintain the functionality of the lung, humans possess a two-layer, extracellular, mucus barrier composed predominantly of individual proteins termed mucins. Additionally, underlying epithelial cells produce interferons upon virus detection that promote the establishment of a local antiviral state through autocrine and paracrine signaling. However, despite these protective measures, IAV continues to cause significant annual morbidity and mortality across the globe. Therefore, we sought to further investigate how specific mucin molecules interact with IAV, and how interferon drives intrinsic antiviral defense in the context of a human airway epithelial (HAE) culture system. By utilizing fluorescently-labeled influenza virus particles we further elucidate the adhesive interactions between mucus and influenza virus while also detailing, for the first time, real-time IAV diffusivity within patient-derived mucus samples. These results reveal that the polymeric structure of mucus greatly influences the mobility of IAV within human secreted mucus. Additionally, we investigate the interaction between influenza virus and tethered mucin 1 (MUC1), finding that MUC1 expression is enhanced by virus-driven inflammation and interferon signaling. Moreover, by establishing a genetically-tractable airway epithelial model, we detail the protective role MUC1 plays in preventing the initial establishment and spread of influenza virus in HAE. Specifically, we find that the loss of MUC1 significantly enhances IAV uptake and spread. Finally, we observe that the directionality of IFN exposure at airway epithelial surfaces impacts the magnitude of protection against IAV and SARS-CoV-2. We then detail the cellular composition of our HAE culture system and define a shared IFN response profile across all HAE component cell types as well as cell type-specific interferon stimulated genes. Together our work provides novel insight into the innate and intrinsic anti-viral properties of the human airway epithelium.Item ESTIMATING RISK OF AIRBORNE INFLUENZA TRANSMISSION IN A CONTROLLED ENVIRONMENT(2019) Bueno de Mesquita, Paul Jacob; Milton, Donald K.; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Pandemic preparedness is weakened by uncertainty about the relative importance of influenza transmission modes, particularly airborne droplet nuclei (aerosols). A human-challenge transmission trial in a controlled environment was conducted to address this uncertainty. Healthy, seronegative volunteer ‘Donors’ (N=52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2) and exposed to seronegative ‘Recipients’ randomized to intervention (N=40) or control (N=35) groups. Intervention recipients wore face shields and hand sanitized frequently to limit large droplet and contact transmission. A transmitted infection, confirmed by serology in a control recipient, yielded a 1.3% SAR overall. This was significantly less than the expected 16% SAR (p <0.001) based on a proof-of-concept study that used half as many Donors and exposure days. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols. The extent to which Donor viral shedding was similar to that of mild, natural infections and may be useful for studying transmission was investigated. The only available aerosol shedding comparison data comes from a population of adults with influenza A H3 infection enrolled on the basis of febrile illness plus cough or sore throat, or positive Quidel QuickVue rapid test (N=83). Systematic differences in case selection compared with Donors yielded more severe cases and introduced bias. To account for differences in illness severity, propensity score matching, stratification, and inverse weighting ultimately demonstrated that the experimental and naturally infected groups were too different to compare without bias. While acknowledging the uncertainty in the generalizability of the current challenge model, observed aerosol shedding and CO2 were used in the rebreathed-air version of the Wells-Riley equation to compute average quantum generation rates (95% CI) 0.029 (0.027, 0.03) and 0.11 (0.088, 0.12) per hour for infected Donors and fine aerosol shedding Donors, respectively. Donors shed 1.4E+5 (1.0E+5, 1.8E+5) airborne viral RNA copies per quantum (ID63). This dissertation provides evidence for airborne transmission, presents a methodology for estimating an airborne dose, and suggests a role for building ventilation in reducing risk and the need for future observational studies to evaluate transmission modes in non-experimental settings with greater generalizability.Item THE CONCORDANCE OF INFLUENZA VACCINATION BEHAVIORS AMONG ADULTS AND CHILDREN RESIDING WITHIN THE SAME HOUSEHOLD IN THE DISTRICT OF COLUMBIA, MARYLAND, AND VIRGINIA(2014) Motley, Danielle Olon; Butler, III, James; Public and Community Health; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Background: The distinctive barking sound of whooping cough and rubella's birth defects highlight vaccinations' importance as a public health initiative and medical advancement of the twentieth century. However, little research examines concordance of influenza vaccination uptake between same-household adults and children. Methods: A secondary data analysis of CDC's 2009 National H1N1 Flu Survey (NHFS) examined concordance between adults' influenza vaccination behaviors and responses to NHFS questions representing HBM constructs with the influenza vaccination of same-household children from the District of Columbia, Maryland, and Virginia (DMV). Results: Concordance existed between influenza vaccination statuses of adults and same-household children. HBM constructs of perceived susceptibility, severity, and the cue to action of physician vaccine recommendation were associated with more vaccinated children. Conclusions: This research highlights adults' influenza vaccination status impact on same-household DMV children. Future research is needed to examine parental influenza vaccination effects on influenza vaccination status of their biological children.Item REASSORTMENT AND GENE SELECTION OF INFLUENZA VIRUSES IN THE FERRET MODEL AND POTENTIAL PLATFORMS FOR IN VIVO REVERSE GENETICS(2014) Angel, Matthew Gray; Perez, Daniel R; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Influenza A virus is a highly infectious agent that cause seasonal epidemics affecting 5-15% of the world population with mild to severe illness and possibly death. While this pathogen represents a significant disease burden to the human population, it can also infect a wide range of animals including swine and land-based poultry, which are thought to serve as intermediate hosts between the human and natural wild aquatic bird reservoir. Here, two viruses, a swine-origin pandemic H1N1 and a seasonal human H3N2 are examined for segment fitness during co-infection of in vivo animal models. In three independent co-infections, reassortment between seasonal and pandemic viruses resulted in the selection of an H1N2 virus with a seasonal PB1 with an otherwise pandemic internal gene constellation. Selection for the seasonal PB1 and NA as well as the pandemic M segment was observed to occur rapidly during segment resolution. As pandemic M gene reassortant strains are being consistently identified in the field, studies were performed to identify the genetic determinants in pandemic M gene selection. Research here shows that both the M1 capsid protein and M2 ion channel from the pandemic virus are sufficient to drive the selection of the entire M segment. As swine represent an important intermediate host for the adaptation of potentially pandemic viruses, including pandemic M gene reassortant strains, alternative DNA and recombinant baculovirus-based platforms are investigated for their ability to generate influenza viruses from porcine polymerase I promoters and serve as potential vaccine candidates. Research here shows that influenza A virus can be rescued de novo using the porcine polymerase I promoter in an eight plasmid system. Furthermore, a single bacmid can be constructed that rescues influenza virus or baculovirus encoding the influenza reverse genetic system in mammalian tissue culture or Sf9 cells, respectively. These represent a new generation of species-tailored vaccine platforms.Item International Externalities in Pandemic Influenza Mitigation(2011) Hutton, Stephen; Cropper, Maureen; Economics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)A serious influenza pandemic could be devastating for the world. Ideally, such a pandemic could be contained, but this may be infeasible. One promising method for pandemic mitigation is to treat infectious individuals with antiviral pharmaceuticals. While most of the benefits from treatment accrue to the country in which treatment occurs, there are some positive spillovers: when one country treats more of its population this both reduces the attack rate in the other country and increases the marginal benefit from additional treatment in the other country. These externalities and complementarities may mean that self-interested rich countries should optimally pay for some AV treatment in poor countries. This dissertation demonstrates the presence of antiviral treatment externalities in simple epidemiological SIR models, and then in a descriptively realistic Global Epidemiological Model (GEM). This GEM simulates pandemic spread between cities through the international airline network, and between cities and rural areas through ground transport. Under the base case assumptions of moderate transmissibility of the flu, the distribution of antiviral stockpiles from rich countries to poor and lower middle income countries may indeed pay for itself: providing a stockpile equal to 1% of the population of poor countries will reduce cases in rich countries after 1 year by about 6.13 million cases at a cost of 4.62 doses per rich-country case avoided. Concentrating doses on the outbreak country is, however, even more cost-effective: in the base case it reduces the number of influenza cases by 4.76 million cases, at the cost of roughly 1.92 doses per case avoided. These results depend on the transmissibility of the flu strain, the efficacy of antivirals in reducing infection and on the proportion of infectious who can realistically be identified and treated.Item Host Molecular Responses in Chickens Infected with an Avian Influenza Virus(2008-11-20) Ramirez-Nieto, Gloria Consuelo; Perez, Daniel R.; Veterinary Medical Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Avian influenza virus has a segmented RNA genome that allows the virus to evolve continuously and generate new strains. Wild birds serve as natural reservoirs of avian influenza virus and provide a potential source for emergence of new viruses, which traverse host barriers and infect new avian or mammalian species. The mechanisms involved in this process are not completely understood. Our main goal is to understand host-pathogen interactions involved in avian influenza pathogenicity. As part of our approach we studied the effect of pre-exposure of chickens to IBDV (infectious bursal disease virus) on host susceptibility to infection, disease progression, and host molecular responses to infection with a mallard H5N2 low pathogenic avian influenza (LPAI) virus. We found that prior exposure of chickens to IBDV led to increased susceptibility to infection with the mallard H5N2 LPAI virus compared to normal chickens. This increased susceptibility allowed us to further adapt the virus to chickens. After 22 passages (P22) in IBDV-pre-exposed chickens, the LPAI virus replicated substantially better than the wild-type (WT) mallard virus in both IBDV-exposed and normal chickens. Interestingly, the P22 virus showed similar levels of replication in the respiratory and intestinal tracts of both groups, although it caused exacerbated signs of disease and severe lesions in the IBDV-pre-exposed group. We suggest that prior IBDV exposure provides a port of entry for avian influenza in an otherwise resistant chicken population. Furthermore, adaptation of avian influenza (AI) in IBDV-exposed chickens may allow for the selection of AI virus strains with expanded tissue tropism. We also studied the effects of host response to H5N2 AI in normal and IBDV-infected birds using high-throughput gene expression analysis. We demonstrated that IBDV-exposed chickens showed less than optimal humoral responses to LPAI infection as well as alterations in local molecular pathways that eventually led to exacerbated disease and death. At the molecular level we found amino acid substitutions in the surface glycoprotein hemagglutinin (HA). Those changes suggest selection for a virus that binds to and replicates more efficiently in chickens. Taken together our results suggest that IBDV-pre-exposure may play a role in exacerbating AI-induced pathogenicity.