Browsing by Subject "Innate immunity"
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Item Concerning Brucella LPS: genetic analysis and role in host- agent interaction(Texas A&M University, 2006-10-30) Turse, Joshua EdwardB rucella lipopolysaccharide is an important component of virulence in brucellosis. Recent research in macrophage models has shown that Brucella LPS does not behave like classical LPS by stimulating potent inflammatory responses. The central hypothesis of this work is that O-antigen is dynamic signaling molecular and participates in complex interactions with the host to promote productive infection. A corollary to this is that the host environment is dynamic, and Brucella has evolved mechanisms to cope with changing environments. In an effort to understand the contribution of Brucella LPS to virulence and pathogenesis, the function of a metabolic locus important in the synthesis of LPS has been demonstrated and complemented. The spontaneous loss of LPS expression has been characterized. Contribution of LPS to acquisition of the host environment in tissue culture and mouse models has been explored. This work demonstrated that genes outside the O-antigen biosynthesis ( manBA) cluster contribute to LPS biosynthesis. Further high frequency mutation involving manBA is partly responsible for observed dissociation of Brucella strains. Finally, work herein attempts to look at the role of LPS in acquisition of the host environment and shows that LPS is important for recruiting particular cell populations within a host model of brucellosis.Item Ethanol-induced toxicity and neurodegeneration in C. elegans(2013-08) Gomez, Lina Maria; Pierce-Shimomura, Jonathan T.Alcohol abuse is an enormous problem causing death and disability to over 43 million people worldwide each year (WHO). Chronic alcohol consumption also contributes to abnormal brain morphology and significant brain volume loss indicative of neurodegeneration. Until there are effective treatments to alter maladaptive behavioral patterns in alcohol abuse, more research is needed to prevent alcohol-induced toxicity and degeneration. We used C. elegans as a model system to identify genetic modulators of alcohol toxicity and explored whether prolonged alcohol exposure damages the nervous system. In our study, we exposed L4-larval stage worms to varying concentrations of ethanol for three days and found a dose-dependent deficit in crawling. Furthermore, we evaluated degeneration by assessing the health of neurons using fluorescent reporters. Compared to the untreated group, we found that ethanol-exposed worms had a significant neurodegeneration. Previous findings using C. elegans have suggested that the innate immune pathway may protect against neurodegeneration caused by drug toxicity (Schreiber & McIntire, 2012). We find that deletion of either the innate immune gene nsy-1 (orthologous to the mammalian ASK-1 MAPKKK) or pmk-1 (orthologous to the mammalian p38 MAPK) caused hypersensitivity to ethanol toxicity. Conversely, boosting innate immune signaling via gain-of-function mutation in nsy-1 produced resistance to ethanol toxicity and ameliorated ethanol-induced cholinergic degeneration. Our findings indicate that prolonged exposure to ethanol leads to both behavioral impairments and neuronal degeneration in C. elegans and that the ASK1/p38 MAP kinase pathway may play a role in ethanol-induced damage to the nervous system.Item Evolutionary and functional analyses of primate genes reveal critical host-virus interactions(2014-12) Meyerson, Nicholas Ryan; Sawyer, Sara L.; Krug, Robert M; Dudley, Jaquelin P; Bull, James J; Ehrlich, Lauren IRViruses exert a tremendous evolutionary pressure on their hosts. By hijacking cellular machinery and resources, viruses have been wildly successful at infecting and propagating throughout all domains of life. In the following dissertation, the interactions between primates and some of the viruses that infect them are examined through an evolutionary lens. I begin by introducing the long-standing battle between mammals and viruses that has raged on for hundreds of millions of years. I propose a theoretical framework to understand how slowly evolving mammals are able to keep pace with rapidly evolving viruses, and how we might use this framework to monitor future virus outbreaks. The core of my analyses stems from an evolutionary concept known as the host-virus arms race. This tug-of-war for survival between hosts and viruses leaves an imprint in the DNA of each organism involved that can be detected using statistical analyses. In Chapter 2, I describe these analyses in great detail and perform many tests to ensure that they are being used and applied appropriately. The remainder of my studies focuses on detecting novel signatures of positive selection in primate genes that are likely caused by ancient host-virus arms races. I characterize the evolutionary history of several primate genes that have been implicated in viral life cycles and provide functional evidence that viruses drove their rapid divergence. In doing so I make three important discoveries. First, I characterize a genetic variant of CD4, the cellular receptor for HIV-1, in an owl monkey species that could make them a viable HIV-1 model system. Second, I show that gorilla-specific mutations in RANBP2, a gatekeeper of the cell nucleus, can inhibit HIV-1 infection. And finally, evolutionary signatures in TRIM25, a component of the innate immune system, revealed its ability to inhibit influenza A virus replication by binding incoming viral ribonucleoproteins.Item Membrane remodeling in epsilon proteobacteria and its impact on pathogenesis(2012-05) Cullen, Thomas Wilson; Trent, Michael Stephen; Whiteley, Marvin; Harshey, Rasika M.; Stevens, Scott W.; O'Halloran, Terry J.Bacterial pathogens assemble complex surface structures in an attempt to circumvent host immune detection. A great example is the glycolipid known as lipopolysaccharide or lipooligosaccharide (LPS), the major surface molecule in nearly all gram-negative organisms. LPS is anchored to the bacterial cell surface by a anionic hydrophobic lipid known as lipid A, the major agonist of the mammalian TLR4-MD2 receptor and likely target for cationic antimicrobial peptides (CAMPs) secreted by host cells (i.e. defensins). In this work we investigate LPS modification machinery in related ε-proteobacteria, Helicobacter pylori and Campylobacter jejuni, two important human pathogens, and demonstrate that enzymes involved in LPS modification not only play a role in evasion of host defenses but also an unexpected role in bacterial locomotion. More specifically, we identify the enzyme responsible for 4'-dephosphorylation of H. pylori lipid A, LpxF. Demonstrating that lipid A depohsphorylation at the 1 and 4'-positions by LpxE and LpxF, respectively, are the primary mechanisms used by H. pylori for CAMP resistance, contribute to attenuated TRL4-MD2 activation and are required for colonization of a the gastric mucosa in murine host. Similarly in C. jejuni, we identify an enzyme, EptC, responsible for modification of lipid A at both the 1 and 4'-positions with phosphoethanolamine (pEtN), also required for CAMP resistance in this organism. Suprisingly, EptC was found to serve a dual role in modifying not only lipid A with pEtN but also the flagellar rod protein FlgG at residue Thr75, required for motility and efficient flagella production. This work links membrane biogenesis with flagella assembly, both shown to be required for colonization of a host and adds to a growing list of post-translational modifications found in prokaryotes. Understanding how pathogens evade immune detection, interphase with the surrounding environment and assemble major surface features is key in the development of novel treatments and vaccines.