Browsing by Subject "Host-pathogen interactions"

Now showing 1 - 3 of 3
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    Counteraction of APOBEC3 Proteins by Herpesvirus Ribonucleotide Reductases
    (2019-08) Cheng, Adam
    The APOBEC3 family of DNA cytosine deaminases plays an important role in antiviral innate immunity. In this thesis, we describe the novel function of APOBEC3B as a physiologic restriction factor against herpesviruses such as Epstein-Barr virus and herpes simplex virus type 1. We additionally define the counteraction mechanism imparted by herpesviruses using the virus-encoded ribonucleotide reductase large subunit. These viral proteins directly bind A3B to inhibit enzymatic activity, relocalize it away from replicating viral DNA, and protect the virus from A3B-mediated hypermutation for preservation of the viral genome. These results have the potential to reveal new modes of antiviral therapy and have implications in the treatment of A3B-driven cancers.
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    Survival strategies of Mycobacterium avium subsp. paratuberculosis in a variety of microenvironments.
    (2012-06) Lamont, Elise A.
    Mycobacteria, specifically Mycobacterium avium subsp. paratuberculosis (MAP), are extreme strategists and as a rule live by deception. Mycobacteria represent a group of closely related acid-fast bacilli that encompass a wide-range of host tropisms and diseases. Mycobacteria can be divided into two complexes: the Mycobacterium tuberculosis complex and the Mycobacterium avium complex (MAC). The MAC is comprised of M. avium subsp. avium (M. avium), MAP, M. intracellulare and M. avium subsp. hominissuis (M. hominissuis), all of which share an over 90 percent nucleotide similarity. Despite its genetic similarity, MAC elicits different diseases in both animals and humans including infections of the lung, lymph nodes, bones, skin and gastrointestinal tract. MAP is a unique member of MAC as it infects and establishes itself within the intestine of ruminants and other wildlife. Furthermore, MAP lives in a quiescent state in soil and aquatic environments. Since MAP encounters numerous environments, including those with unfavorable conditions, it has developed several strategies to survive. However, the mechanisms by which MAP survival is achieved remains incompletely understood. The goal of these studies was to determine how MAP may survive and disseminate under unfavorable conditions, which included nutrient starvation and host pressures. We have identified the development of a new MAP morphotype under prolonged nutrient starved conditions. This novel MAP morphotype resembles a spore-like structure and contains dipicolinic acid, which is used to protect DNA located within the core. These novel structures are heat resistant at 70oC and can be enriched for in multiple MAP strains. Furthermore, we describe an unrecognized mechanism by which MAP takes advantage of host responses at the epithelium interface to recruit macrophages to the site of initial infection. MAP is able to safely enter into macrophages and consequently ensures its establishment, survival and dissemination throughout the host. Lastly, we demonstrate the importance of host physiological relevant temperature on successful disease progression. Infection utilizing the temperature of MAP’s natural host, the cow, enhances the speed of infection as well as host and pathogen transcriptomic profiles. Taken together, data generated from these studies will provide the basis for understanding MAP persistence and survival in diverse conditions. The mechanisms by which MAP establishes, disseminates and/or survives difficult conditions may impact new programs to control JD as well as rational vaccine/therapeutic design and the way in which we view other mycobacterioses.
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    Unraveling the genetic determinants of virulence in Cryptococcus neoformans
    (2023-06) Jackson, Katrina
    Cryptococcus neoformans is a fungal pathogen that causes meningitis, primarily in patients who are immunocompromised. It is most common in populations with advanced HIV disease in low- and middle-income countries, especially in sub–Saharan Africa, South America, and southeast Asia. Even with improvements in treatments, the mortality rate remains unacceptably high. Mortality is associated with both host and pathogen specific factors, including C. neoformans genetic background. C. neoformans has three major lineages: VNI, VNII, and VNB. VNI and VNII are both clonal and globally distributed, with the vast majority of disease caused by VNI. VNB is highly diverse and regional; disease caused by VNB isolates tends to be associated with worse outcomes. Isolates are further divided into sequence types (STs), based on an accepted multi-locus sequence typing scheme. In the last decade, several studies have linked ST to patient outcome, with some STs found to be more virulent than others. When genetically matched mice were infected with patient isolates, mortality was significantly associated with patient mortality, showing that isolate genetic background is important for strain specific mortality. The reasons for the link between patient outcome and isolate genetic background remain unclear. This thesis aims to identify mutations and genes associated with changes in virulence in both patients and mice, understand the evolutionary patterns of virulence-related mutations, and explain the mouse immune response associated with a hypervirulent disease manifestation.