Repository logo

Theses and Dissertations

Permanent URI for this collection

https://hdl.handle.net/10217/100474

Browse

Browsing Theses and Dissertations by Subject "aerosol"

Now showing 1 - 3 of 3
  • Thumbnail Image
    ItemOpen Access
    Cationic liposome-DNA complex-based immunotherapeutic and immunization strategies for control of la Crosse virus and Leishmania major infections
    (Colorado State University. Libraries, 2011) Arthun, Erik Norden, author; Dow, Steven, advisor; Foy, Brian, committee member; Lappin, Michael, committee member; Callan, Robert, committee member
    To view the abstract, please see the full text of the document.
  • Thumbnail Image
    ItemOpen Access
    Oral and nasal mucosal pathways of prion infection in chronic wasting disease
    (Colorado State University. Libraries, 2010) Denkers, Nathaniel David, author; Hoover, Edward Arthur, 1942-, advisor; Zabel, Mark Douglas, committee member; Suchman, Erica, committee member; Ross, Eric D., committee member
    Chronic wasting disease (CWD) is a fatal neurodegenerative prion disease of deer, elk, and moose. The unique feature of CWD as a prion disease is its efficient transmission among cervids in nature. As with other prion infections, CWD disease inception relies on the conversion of the normal host cellular prion protein (PrPC) to the abnormal, protease-resistant isoform (PrPCWD)--the diagnostic hallmark of prion diseases. Since its detection in Colorado in 1967, CWD has spread to captive and free-ranging cervid species in 16 additional states, 3 Canadian provinces, and one Asian country. CWD is also exceptional as the only prion disease to afflict a free-ranging, wildlife population. Understanding the facile means by which CWD is transmitted from animal to animal is important not only in understanding prion transmission overall but also in elucidating the potential public health consequences of cross species prion transmission. This dissertation work asks whether and how CWD prions are able to cross the oral and nasal mucosa to induce infection and disease. The above questions were addressed through the use of two strains of transgenic mice that express the normal cervid prion protein [Tg(CerPrP)1536, Tg(CerPrP-E226)5037+/-] and prion protein knockout mice [FVB PrP0/0] exposed by either aerosol, nasal, or oral route to CWD prions. In the first series of studies, cohorts of Tg(CerPrP)1536 mice were exposed to brain homogenates from either CWD-infected or CWD-naïve deer via either aerosolization or direct nasal installation. In the second series of studies, cohorts of Tg(CerPrP-E226)5037+/- mice were exposed to the same inocula via installation onto the lingual mucosal surface which had or had not been previously subjected to superficial abrasions. Mice were then observed and tissues from each cohort, at time points ranging from weeks to as long as 2 years post inoculation, were examined for the presence of the abnormal prion protein of CWD (PrPCWD) using western blotting and immunohistochemistry assays. The final studies employed the same inoculation techniques used in the first two studies to seek to identify early (less than 4 hours) sites of prion entry via the mucous membranes. The results of these dissertation studies demonstrated; 1) that CWD could be transmitted by aerosol exposure with high efficiency compared with direct inoculation onto the nasal mucosa; and 2) that micro-abrasions to the lingual surface greatly facilitated CWD prion transmission. Finally and perhaps surprisingly, we were unable to detect PrPCWD in either the nasal or oral mucosa shortly after inoculation or at any time, even after the onset of clinical symptoms of CWD. The results from these studies suggest that; 1) CWD prions can be transmitted by aerosol exposure; thus exposure to the respiratory system merits increased consideration in prion transmission and biosafety; 2) minor oral mucosal injury does greatly facilitate prion infection--a potentially significant co-factor in CWD transmission of foraging cervids; and 3) these mucosal pathways may explain how and why CWD is transmitted with high efficiency in animals exposed to low concentrations of prions in nature.
  • Thumbnail Image
    ItemOpen Access
    The development and characterization of caprine infection models of melioidosis
    (Colorado State University. Libraries, 2012) Soffler, Carl, author; Bowen, Richard A., advisor; Aboellail, Tawfik A., committee member; Dow, Steven S., committee member; Schweizer, Herbert P., committee member; Van Metre, David C., committee member
    Melioidosis, the disease resulting from infection with Burkholderia pseudomallei, is a serious emerging infectious disease endemic to Southeast Asia and Northern Australasia and a leading infectious cause of death in the former. Additionally, B. pseudomallei has been designated a Category B Select Agent by the United States Centers for Disease Control and Prevention because of its potential use in bioterrorism, which has led to intensive research on inhalational models of murine melioidosis. Natural infection is believed to occur predominantly through percutaneous inoculation or inhalation in the rainy season in endemic areas, with infection following oral exposure occurring to a lesser extent. However, the actual importance of each route of infection in natural disease is unknown. Studies examining the comparative pathogenesis of melioidosis in regards to the route of infection are generally lacking, particularly in naturally affected species. A goat model was selected as it provides the opportunity to study the importance of the route of infection and its effect on disease pathogenesis in a naturally affected species. Disease and outcome can be evaluated relative to natural presentations in both human and goat populations as goats and humans exhibit a similar epizootiology/epidemiology of melioidosis, which corresponds to similar environmental exposure to B. pseudomallei within its endemic range. Furthermore, the larger body size of goats allows for human-relevant clinical monitoring as well as longer-term serial evaluation of disease progression and therapy in individual animals. Using a caprine model system, we have investigated the pathogenesis of infection following intratracheal aerosol and percutaneous exposure to 104 delivered colony forming units (CFU) of B. pseudomallei. Disease was observed in all animals following infection. Acute disease was more severe in aerosol infected goats, but both groups tended to develop subacute to chronic active disease, with percutaneously infected goats showing regression of lesions at the later time points. Percutaneously infected goats generally exhibited more variable clinical signs, hematologic changes, and gross pathology, but often had histologic lesions with more severe changes. Dissemination from the site of infection was much more rapid in the percutaneously infected animals, with bacteria detectable in the lungs and spleen as early as Day 2 post-infection (PI) and gross abscessation evident in distant sites as early as Day 7 PI. Extrapulmonary dissemination after aerosol infection appeared to occur around Day 7 with splenic or renal abscesses not grossly detectable until day 14. Lesion development was closely associated with a leukocytoclastic vasculitis observed in affected tissues in both aerosol and percutaneous infection. Pulmonary involvement was evident in all but one percutaneously infected goat (Day 2 PI) by culture or the presence of histologic lesions. The rapid dissemination of B. pseudomallei after percutaneous inoculation challenges the perception that inhalational melioidosis is more severe in presentation or will affect the lungs more frequently than percutaneous infection. The findings presented here provide a detailed clinical, radiographic, and pathologic description of the pathogenesis of subacute to chronic aerosol and percutaneous caprine melioidosis. However, acute presentations are possible in association with concurrent disease or debility, suggesting that the caprine model system may be amenable to the incorporation of risk factors to increase susceptibility/acute disease as typically seen in human melioidosis. It is hoped these models will help broaden the scope of melioidosis research to fill remaining voids, particularly in the areas immunology, vaccine development, and evaluation of novel antimicrobial therapeutics through the comparative study of disease. Additionally, melioidosis in goats remains a current problem in the regions of Southeast Asia and Northern Australia with enzootic and epizootic disease causing economic losses. Any knowledge gained from the use of these models in regards to improved diagnosis, preventive measures, and vaccination could be directly applicable to the management of these goat populations and advancing public health.