Rozprawy doktorskie: „Bacterial metabolism and pathogenesis”

1

Haque, Md Risat Ul. "Bacterial nitric oxide metabolism in the pathogenesis of meningococcal sepsis". Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/12201/.

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Neisseria meningitidis is the causative agent of fatal meningococcal sepsis in humans, characterised by high bacterial loads in blood, and collapse of the microcirculatory system. The organism is adapted to colonise the human nasopharynx, an environment which is oxygen poor but rich in nitric oxide (NO), a gas vital for the regulation of essential physiological processes such as vasorelaxation, antimicrobial and innate immune responses by the host. Furthermore, during sepsis caused by meningococcaemia, high concentrations of nitrite can be measured in the blood, derived from activated circulating monocytes and endothelial cells. Meningococci express a partial denitrification pathway comprising of a nitrite reductase (AniA) and a nitric oxide reductase (NorB) to survive and thrive in an oxygen deficient niche such as the nasopharynx. The aniA and norB genes are negatively regulated by an NO sensitive repressor, NsrR. Studies from our group have shown that NorB is critical for counteracting the antimicrobial and innate immune response of the host. As NO based regulation requires a tightly regulated equilibrium, this could have far reaching consequences on the NO mediated signalling processes, and is likely to be relevant to survival of the organism within NO-enriched nasopharyngeal mucosae and blood. Previously, it was shown that bacterial NO detoxification reduces the concentration of host-cell S-nitrosothiol (SNO), a vital post-translational modification akin to phosphorylation, in murine macrophages in vitro. To investigate if similar meningococcal NO metabolism mediated SNO depletion persists in vivo, we established a murine model of early acute meningococcal sepsis. We showed that bacterial burden correlates positively with plasma SNO and hepatic NO2- but negatively with hepatic NOx. However, bacterial NO metabolism did not differentially modulate SNO and other NO metabolite profile of murine blood and liver tissue. Since there is no information to date on the effect of multiple meningococcal denitrification genes (aniA and norB) on the cellular pathology of meningococcal sepsis, we constructed and characterised a combination of NO metabolising gene mutants (ΔaniA/ΔnorB, ΔnsrR/ΔnorB, ΔaniA/ΔnorB/ΔnsrR) using the isocloning method. Differentiated human primary bronchial airway epithelial cells cultured at an air-liquid interface (HPEC-ALI) are polarised cells with tight junctions, possessing similar characteristics to the nasopharyngeal epithelial cells with which meningococci have to interact during colonisation and pathogenesis. HPEC-ALIs were infected with the newly created mutants (ΔaniA/ΔnorB and ΔaniA/ΔnorB/ΔnsrR) to examine the role of bacterial NO metabolism on the barrier function and immune response, functions known to be modulated by high concentrations of NO present in the airway epithelium. We demonstrated bacterial burden inversely correlates with the barrier function (TER) but positively with the cytokine profile (IL-8, TNFα). However, meningococcal denitrification does not have any differential role in the regulation of barrier function and cytokine profile of the HPEC-ALIs in the experimental system we used. The role of meningococcal denitrification in biofilm formation in vitro was also investigated. Preliminary data showed when biofilm formation was induced by nutrient starvation, ΔaniA/ΔnorB showed a significantly reduced biofilm forming ability compared to the Wt strain measured by the crystal violet staining. To investigate the role of aniA in differential regulation of biofilm formation, reverse complemented strains (ΔaniA/aniAIPTG+ and ΔaniA/aniA+) were created. Characterisation data showed functional activation was restored in ΔaniA when aniA was complemented along with the upstream regulatory elements such as the endogenous promoter (ΔaniA/aniA+) but not when aniA coding region was complemented under the control of an IPTG inducible lac promoter (ΔaniA/aniAIPTG+).

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2

Cordes, Frank Stephan. "Biophysical studies of bacterial pathogenesis". Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404113.

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Borodina, Elena. "Bacterial metabolism of dimethylsulfone". Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251998.

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Green, Luke Richard. "The role of teraspanins in bacterial pathogenesis". Thesis, University of Sheffield, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522436.

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Kaittanis, Charalambos. "Magnetic nanosensors for multiplexed bacterial pathogenesis identification". Doctoral diss., University of Central Florida, 2010. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4610.

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Developing diagnostic modalities that utilize nanomaterials and miniaturized detectors can have an impact in point-of-care diagnostics. Diagnostic systems that (i) are sensitive, robust, and portable, (ii) allow detection in clinical samples, (iii) require minimal sample preparation yielding results quickly, and (iv) can simultaneously quantify multiple targets, would have a great potential in biomedical research and public healthcare. Bacterial infections still cause pathogenesis throughout the world (Chapter I). The emergence of multi-drug resistant strains, the potential appearance of bacterial pandemics, the increased occurrence of bacterial nosocomial infections, the wide-scale food poisoning incidents and the use of bacteria in biowarfare highlight the need for designing novel bacterial-sensing modalities. Among the most prominent disease-causing bacteria are strains of Escherichia coli, like the E. coli O157:H7 that produces the Shiga-like toxin (Stx). Apart from diarrheagenic E. coli strains, others cause disease varying from hemolytic uremic syndrome and urinary tract infections to septicemia and meningitis. Therefore, the detection of E. coli needs to be performed fast and reliably in diverse environmental and clinical samples. Similarly, Mycobacterium avium spp. paratuberculosis (MAP), a fastidious microorganism that causes Johne's disease in cattle and has been implicated in Crohn's disease (CD) etiology, is found in products from infected animals and clinical samples from CD patients, making MAP an excellent proof-of-principle model. Recently, magnetic relaxation nanosensors (MRnS) provided the first applications of improved diagnostics with high sensitivity and specificity.; Furthermore, these MRnS achieved equally fast IS900 detection even in crude DNA extracts, outperforming the gold standard diagnostic method of nested Polymerase Chain Reaction (nPCR). Likewise, the MRnS detected IS900 with unprecedented sensitivity and specificity in clinical isolates obtained from blood and biopsies of CD patients, indicating the clinical utility of these nanosensors. Subsequently, we designed MRnS for the detection of MAP via surface-marker recognition in complex matrices (Chapter III). Milk and blood samples containing various concentrations of MAP were screened and quantified without any processing via MRnS, obtaining dynamic concentration-dependent curves within an hour. The MAP MRnS were able not only to identify their target in the presence of interferences from other Gram positive and Gram negative bacteria, but could differentiate MAP among other mycobacteria including Mycobacterium tuberculosis. In addition, detection of MAP was performed in clinical isolates from CD patients and homogenized tissues from Johne's disease cattle, demonstrating for the first time the rapid identification of bacteria in produce, as well as clinical and environmental samples. However, comparing the unique MAP quantification patterns with literature-available trends of other targets, we were prompted to elucidate the underlying mechanism of this novel behavior (Chapter IV). We hypothesized that the nanoparticle valency--the amount of probe on the surface of the MRnS --may have modulated the changes in the relaxation times (delta]T2) upon MRnS--target association. To address this, we prepared MAP MRnS with high and low anti-MAP antibody levels using the same nanoparticle formulation. Results corroborated our hypothesis, but to further bolster it we investigated if this behavior is target-size-independent.; Hence utilizing small-molecule- and antibody-carrying MRnS, we detected cancer cells in blood, observing similar detection patterns that resembled those of the bacterial studies. Notably, a single cancer cell was identified via high-valency small-molecule MRnS, having grave importance in cancer diagnostics because a single cancer cell progenitor in circulation can effectively initiate the metastatic process. Apart from cells, we also detected the Cholera Toxin B subunit with valencly-engineered MRnS, observing similar to the cellular targets' diagnostic profiling behavior. Finally, as bacterial drug resistance is of grave healthcare importance, we utilized MRnS for the assessment of bacterial metabolism and drug susceptibility (Chapter V). Contrary to spectophotometric and visual nanosensors, their magnetic counterparts were able to quickly assess bacterial carbohydrate uptake and sensitivity to antibiotics even in blood. Two MRnS-based assay formats were devised relying on either the Concanavalin A (Con A)-induced clustering of polysaccharide-coated nanoparticles or the association between free carbohydrates and Con A-carrying MRnS. Overall, taking together these results, as well as those on pathogen detection and the recent instrumentation advancements, the use of MRnS in the clinic, the lab and the field should be anticipated.; Nucleic acids, proteins, viruses and enzymatic activity were probed, yet neither large targets (for instance bacterial and mammalian cells) nor multiple bacterial disease parameters have been simultaneously monitored, in order to provide thorough information for clinical decision making. Therefore, the goal of this study was to utilize MRnS for the sensitive identification of multiple targets associated with bacterial pathogenesis, while monitoring virulence factors at the microorganism, nucleic acid and virulence factor levels, to facilitate improved diagnosis and optimal treatment regimes. To demonstrate the versatility of MRnS, we used MAP as our model system, as well as several other pathogens and eukaryotic cell lines. In initial studies, we developed MRnS suitable for biomedical applications (Chapter II). The resulting MRnS were composed of an iron oxide core, which was caged within a biodegradable polymeric coating that could be further functionalized for the attachment of molecular probes. We demonstrated that depending on the polymer used the physical and chemical properties of the MRnS can be tailored. Furthermore, we investigated the role of polymer in the enzyme-mimicking activity of MRnS, which may lead to the development of optimized colorimetric in vitro diagnostic systems such as immunoassays and small-molecule-based screening platforms. Additionally, via facile conjugation chemistries, we prepared bacterium-specific MRnS for the detection of nucleic acid signatures (Chapter III). Considering that MAP DNA can be detected in clinical samples and isolates from CD patients via laborious isolation and amplification procedures requiring several days, MRnS detected MAP's IS900 nucleic acid marker up to a single MAP genome copy detection within 30 minutes.
ID: 028916614; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Thesis (Ph.D.)--University of Central Florida, 2010.; Includes bibliographical references (p. 139-150).
Ph.D.
Doctorate
Burnett School of Biomedical Sciences
Medicine

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Vdovikova, Svitlana. "Roles of membrane vesicles in bacterial pathogenesis". Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Medicinska fakulteten), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-138714.

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The production of membranous vesicles is observed to occur among organisms from all domains of the tree of life spanning prokaryotes (bacteria, archaea) and eukaryotes (plants, animals and fungi). Bacterial release of membrane-derived vesicles (MVs) has been studied most extensively in cases of Gram-negative species and implicating their outer membrane in formation of extracellular MVs. However, recent studies focusing on Gram-positive bacteria have established that they also undergo MV formation. Membrane vesicles are released during normal bacterial growth, they are derived from the bacterial membrane(s) and may function as transporters of different proteins, DNA and RNA to the neighbouring bacteria or to the cells of a mammalian host. The transport of virulence factors in a condensed manner via MVs to the host cells presumably protects these proteins from degradation and, thereby, targets the host cells in a specific manner. The aim of my thesis is to investigate secretion of MV-associated virulence factors and to study interactions of MVs produced by two selected Gram-negative and Gram-positive bacteria, i.e. Vibrio cholerae and Listeria monocytogenes, with eukaryotic host cells. Depending on whether the bacterium acts as an extracellular or intracellular pathogen, MVs may be considered to have specific functions, which may lead to the different outcomes of MV-host interactions. V. cholerae transport systems for virulence factors include the Type VI secretion system and MVs (also referred to as the “Type 0” secretion system). We have identified that the biologically active form of PrtV protease in different V. cholerae serogroups is transported via MVs. PrtV protease is essential for V. cholerae environmental survival and protection from natural predator grazing. We demonstrated that PrtV is primarily translocated via the inner membrane to the periplasmic space, where it undergoes autoproteolysis, and the truncated version of PrtV protein is packaged inside the MVs and released from the surface of bacteria. MV-associated PrtV protease showed a contribution to bacterial resistance towards the antimicrobial peptide LL-37, thereby, enhancing bacterial survival by avoiding this innate immune defense of the host. We also studied another virulence factor of V. cholerae, the pore-forming toxin VCC, which was found to be transported by MVs. MV-associated VCC is biologically active and triggers an autophagic response in the target cells. We suggested that autophagy serves as a cellular defense mechanism against the MV-associated bacterial virulence factor of V. cholerae. Listeria monocytogenes is a Gram-positive intracellular and facultative anaerobic food-borne pathogen causing listeriosis. It causes only sporadic outbreaks in healthy individuals, however, it is dangerous for a fetus or newborn child, and for pregnant and immunocompromised people, leading to a deadly infection in one third of the cases. We have analyzed MVs produced by L. monocytogenes and their interaction with eukaryotic cells. Confocal microscopy analysis showed that MVs are internalized into HeLa and HEK293 cells and are accumulated in lysosomes. Moreover, L. monocytogenes produces MVs inside the host cells and even inside the phagosomes. We found that the major virulence factor of L. monocytogenes, the cholesterol-dependent pore-forming protein listeriolysin O (LLO), is entrapped inside the MVs and resides there in an oxidized inactive state. LLO is known to induce autophagy by making pores in the phagosomal membrane of targeted eukaryotic cells. In our studies, we have shown that MVs effectively abrogated autophagy induced by Torin1, by purified LLO or by another pore-forming toxin from V. cholerae. We also found that MVs promote bacterial intracellular survival inside mouse embryonic fibroblasts. In addition, MVs have been shown to have a strong protective activity against host cell necrosis initiated by pore-forming toxin. Taken together, these findings suggested that in vivo MVs production from L. monocytogenes might be a relevant strategy of bacteria to manipulate host responses and to promote bacterial survival inside the host cells.

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Woods, Nigel R. "The bacterial metabolism of propane". Thesis, University of Warwick, 1988. http://wrap.warwick.ac.uk/98056/.

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A range of enrichment/isolation procedures yielded over 80 strains of Gram-positive propane-utilizing bacteria from a variety of environments. All appeared to be members of the Corynebacterium-Mycobacterium-Nocardia complex. No Gram-negative organisms were isolated and screening of Pseudomonas spp. culture collections failed to isolate any gaseous alkane-utilizing strains. Three of the isolated strains, identified as Rhodococcus rhodochrous. R. erythropolis and a Mycobacterium sp., were subjected to further analyses. They showed differing specificities towards gaseous alkane substrates, R. rhodochrous growing only on propane, the Mycobacterium sp. on ethane and propane, and R. erythropolis on all three. None could grow on alkenes but all could epoxidate propene to 1,2-epoxypropane after growth on propane. R. rhodochrous (designated strain PNKbl) was selected for detailed study. Its potential to epoxidate alkenes was investigated further. Attempts to grow the organism in steady-state, continuous culture on propane were unsuccessful. It grew batchwise on most of the putative Intermediates of propane metabolism. Simultaneous adaptation studies using whole cells suggested that the organism had the potential to use either the terminal or subterminal pathways of propane metabolism. SDS-polyacrylamide gel electrophoresis revealed proteins of molecular weight 67, 59, 57 kDal specific to cells grown on propane, which may be components of the propane-oxidizing system. Oxygenase activity induced by propane, was studied in whole cell and cell-free systems and results suggest that it may be different in nature to those previously described alkane oxygenase systems. The enzyme complement of propane-grown cells suggested that propane could be assimilated by either terminal or subterminal oxidation pathways and the relative importance of each remains unclear.

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Erdlenbruch, Barbara Nicole Susanne. "Bacterial metabolism of short chain alkanesulfonates". Thesis, University of Warwick, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250990.

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de, Klerk Nele. "Host-bacteria interactions : Host cell responses and bacterial pathogenesis". Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-126425.

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Helicobacter pylori colonizes the human stomach, where it causes gastritis that may develop into peptic ulcer disease or cancer when left untreated. Neisseria gonorrhoeae colonizes the urogenital tract and causes the sexually transmitted disease gonorrhea. In contrast, Lactobacillus species are part of the human microbiota, which is the resident microbial community, and are considered to be beneficial for health. The first host cell types that bacteria encounter when they enter the body are epithelial cells, which form the border between the inside and the outside, and macrophages, which are immune cells that engulf unwanted material. The focus of this thesis has been the interaction between the host and bacteria, aiming to increase our knowledge of the molecular mechanisms that underlie the host responses and their effects on bacterial pathogenicity. Understanding the interactions between bacteria and the host will hopefully enable the development of new strategies for the treatment of infectious disease. In paper I, we investigated the effect of N. gonorrhoeae on the growth factor amphiregulin in cervical epithelial cells and found that the processing and release of amphiregulin changes upon infection. In paper II, we examined the expression of the transcription factor early growth response-1 (EGR1) in epithelial cells during bacterial colonization. We demonstrated that EGR1 is rapidly upregulated by many different bacteria. This upregulation is independent of the pathogenicity, Gram-staining type and level of adherence of the bacteria, but generally requires viable bacteria and contact with the host cell. The induction of EGR1 is mediated primarily by signaling through EGFR, ERK1/2 and β1-integrins. In paper III, we described the interactions of the uncharacterized protein JHP0290, which is secreted by H. pylori, with host cells. JHP0290 is able to bind to several cell types and induces apoptosis and TNF release in macrophages. For both of these responses, signaling through Src family kinases and ERK is essential. Apoptosis is partially mediated by TNF release. Finally, in paper IV, we showed that certain Lactobacillus strains can reduce the colonization of H. pylori on gastric epithelial cells. Lactobacilli decrease the gene expression of SabA and thereby inhibit the binding mediated by this adhesin.

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.

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Gonçalves, Carla Aguiar. "The role of polyunsaturated fatty acids in bacterial pathogenesis". Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13794.

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Mestrado em Biotecnologia
Polyunsaturated fatty acids (PUFAs) comprise a class of essential micronutrients, which are essential for normal development, cardiovascular health, and immunity. The role of lipids, including long-chain fatty acids, in the immune response is increasingly being recognized as beneficial regulators of the immune systems. However, the mechanisms by which PUFAs modulate innate immunity are yet to be fully clarified. C. elegans has been used in several recent studies as a simple animal model for the study of host-pathogen interactions, generating important insights into both bacterial pathogenesis and host innate immunity. Many of the virulence mechanisms used by bacterial pathogens to cause disease in mammalian hosts have also been shown to be important for pathogenesis in C. elegans and, similarly, important features of the host innate immunity have been evolutionarily conserved between C. elegans and mammals. This project is focused on addressing the role of polyunsaturated fatty acids in bacterial pathogenesis using C. elegans as model system. We find that knockdown of some elongase genes increase the worms’ susceptibility towards infection with the adherent-invasive Escherichia Coli LF82, isolated from a patient suffering from Crohn’s disease. Moreover, dietary supplementation with the fatty acid γ-linolenic acid rescued the enhanced pathogen susceptibility of C. elegans lacking a Δ6 desaturase. The fatty acid profile of the nematode is altered upon infection with pathogenic LF82. qRT-PCR analysis allowed to determine that stress and autophagy genes are induced in C. elegans infected with this particular type of E. coli. Autophagy was found to be increased on C. elegans challenged with LF82, as determined by fluorescence microscopy. Collectively these results suggest an important role for PUFAS in the innate immune response and indicate that autophagy may have a contribution for C. elegans response towards the pathogen E. coli LF82.

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Osborn, Lucas Jerry. "MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS". Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241.

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Baker, Genevieve Elizabeth. "Molecular insights into bacterial fatty acid metabolism". Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715811.

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Kimmitt, Patrick Thomas. "Expression of Shiga toxin genes in Escherichia coli". Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299614.

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O'Sullivan, A. M. "Microbial factors influencing the pathogenesis of Campylobacter infections". Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378924.

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Matts, Paul Jonathan. "Bacterial metabolism of short-chain alkyl sulphate esters". Thesis, Cardiff University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304974.

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Ferreira, Patrícia Daniela Oliveira. "Regulation of iron metabolism in different bacterial infections". Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/14598.

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Mestrado em Biomedicina Molecular
Iron is found in almost all living organisms, playing a central role in host-pathogen interactions and being crucial for both host and pathogens. In the host, iron is a crucial element, since it plays a key role in biological processes such as oxygen transport, biosynthesis of DNA, energy production and regulation of gene expression. However, high concentrations of iron can also be toxic to cells due to the ability to generate hydroxyl radicals. Thus, vertebrates developed proteins to transport and store iron: transferrin and ferritin, respectivetly. Hepcidin is a key protein of iron metabolism, since it binds to ferroportin, the iron exporter, regulating the release of iron to the serum. On the other hand, iron is also fundamental for pathogens that required it to its growth and proliferation, to the expression of virulence factors and to metabolic processes. Thereby, during infection, the host and the pathogen compete by this metal. Pathogens developed multiple strategies to acquire iron from the host during infection. Thus, making iron unavailable for microorganisms is a central mechanism in host defense. In this work, we investigated the regulation of iron metabolism in host during infection with Listeria monocytogenes, a gram-positive bacterium and Salmonella Typhimurium, a gram-negative bacterium in order to verify whether there are alterations in host iron metabolism depending of infection type and if hepcidin have a central role in these alterations. C57BL6 male mice were infected with 104 CFU of L. monocytogenes, S. Typhimurium, or an equivalent volume of vehicle and sacrificed at different time points. Bacterial load quantification, non-heme iron determination in liver, evaluation of iron distribution in tissue, histopathologic analyses and the expression of genes related with iron metabolism were analyzed. Our results show that in both infections with L. monocytogenes and S. Typhimurium the host immune system are not able to irradiate the infection and, thus, the bacterial load increases during the experiment. Regarding the hematological and serological parameters, a reduction of red blood cells and hematocrit is observed, as well as, of serum iron levels. The levels of interleukin-6 and hepcidin increase at different time points in each infection. Additionally, non-heme iron concentration increases in liver during infection with both pathogens. Histopathological alterations were also detected during infection with L monocytogenes and S. Typhimurium. Our data suggests that both infections induce alterations in host iron metabolism. However, the infection with S. Typhimurium appears to have earlier and more severe effects in the host than infection with L. monocytogenes.
O ferro é encontrado em quase todos os seres vivos, desempenhando um papel central nas interacções entre o hospedeiro e o patógeno e sendo essencial para ambos. Para o hospedeiro, o ferro é um elemento crucial, uma vez que desempenha um papel chave em processos biológicos como o transporte de oxigénio, a biossíntese de DNA, produção de energia e regulação da expressão génica. No entanto, elevadas concentrações de ferro também podem ser tóxicas para as células devido à capacidade de gerarem radicais hidroxilo. Assim, os vertebrados possuem proteínas para transportar e armazenar o ferro, a transferrina e a ferritina respetivamente. A hepcidina é uma proteína chave do metabolismo do ferro, uma vez que se liga à ferroportina, o exportador do ferro, regulando a libertação de ferro para o soro. Por outro lado, o ferro é também fundamental para os patógenos, que o requerem para o seu crescimento e proliferação, para a expressão de factores de virulência e para vários processos metabólicos. Assim, durante a infecção, o hospedeiro e o patógeno competem por este metal. Os patógenos desenvolveram múltiplas estratégias para adquirir o ferro a partir do hospedeiro durante a infeção. Deste modo, tornar o ferro indisponível para os microrganismos é um mecanismo central na defesa do hospedeiro. Neste trabalho, investigámos a regulação do metabolismo do ferro no hospedeiro durante a infecção com Listeria monocytogenes, uma bactéria gram-positiva e com Salmonella Typhimurium, uma bactéria gram-negativa, de modo a verificar se existem alterações no metabolismo do ferro do hospedeiro dependendo do tipo de infeção e se a hepcidina tem um papel preponderante nestas alterações. Murganhos machos C57BL6 foram infectados com 104 CFU de L. monocytogenes, S. Typhimurium, ou um volume equivalente de veículo e sacrificados a diferentes tempos experimentais. A quantificação da carga bacteriana, determinação do ferro não hémico no fígado, avaliação da distribuição de ferro no tecido, análise histopatológica e a expressão de genes relacionados com o metabolismo do ferro foram analisados. Os nossos resultados mostram que tanto na infeção com L. monocytogenes como na infeção com S. Typhimurium, o sistema imunitário do hospedeiro não é capaz de irradiar a infeção e, assim, a carga bacteriana aumenta durante a experiência. Em relação aos parâmetros hematológicos e serológicos, é observada a redução da quantidade de eritrócitos e do hematócrito, bem como dos níveis de ferro no soro. Os níveis de interleucina-6 e de hepcidina aumentam em diferentes tempos experimentais em cada infeção. Adicionalmente, a concentração de ferro não hémico aumenta no fígado durante a infeção com ambos os patógenos. Foram também detetadas alterações histopatológicas aquando da infeção com L monocytogenes e S. Typhimurium. Os nossos dados sugerem que ambas as infeções induzem alterações no metabolismo do ferro do hospedeiro. Contudo, a infeção com S. Typhimurium parece ter efeitos mais precoces e mais severos no hospedeiro do que a infeção com L. monocytogenes.

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Wiskur, Brandt Justin. "Pathogenesis of Klebsiella pneumoniae endophthalmitis". Oklahoma City : [s.n.], 2008.

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Garza-Mayers, Anna Cristina. "Characterization of host and bacterial factors critical for Shigella flexneri pathogenesis". Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13064818.

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Shigella species are Gram-negative bacterial pathogens acquired by fecal-oral spread. A common cause of bacillary dysentery worldwide, particularly in developing countries, Shigella invade colonic mucosal cells and employ a repertoire of proteins secreted by a type III secretion system (T3SS) to manipulate host cytoskeleton and signaling pathways. The bacterium escapes from the vacuole, enters the host cell cytoplasm, evades host recognition, and spreads intercellularly. In this thesis, I describe two independent projects that aim to clarify the complex interplay between bacterial effectors and host processes critical to Shigella flexneri pathogenesis. Primarily, I examined the role of host small GTPase ADP-ribosylation factor 6 (ARF6) in S. flexneri entry. ARF6 functions in membrane trafficking at the plasma membrane and activates membrane ruffle formation. I show here that ARF6 is required for efficient entry, and together with the host guanine nucleotide exchange factor (GEF) ARF nucleotide binding site opener (ARNO) and the T3SS effector IpgD, constitutes a positive feedback loop that amplifies ARF6 activation at S. flexneri entry sites to promote efficient bacterial uptake. I also investigated the outer Shigella protein C (OspC) effectors OspC1, OspC2, and OspC3, highly homologous T3SS effectors with potentially disparate functions. Preliminary evidence suggested that OspC2 and/or OspC3 interact with host protein Toca-1, which is implicated in actin polymerization and pathogen recognition by host innate immune processes. My evidence suggests the OspC proteins are important for evasion of autophagy and/or other mechanisms of intracellular survival and replication. This work identifies new cellular targets and activities of the Shigella effector IpgD and provides insight into mechanisms of pathogenesis dependent on secreted bacterial effectors. The lines of investigation presented here demonstrate the intricate ways in which S. flexneri both exploits and subverts host processes in order to survive in the intracellular environment.

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Rosario, Sarah. "Bacterial Selenoproteins: A Role in Pathogenesis and Targets for Antimicrobial Development". Doctoral diss., University of Central Florida, 2009. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/2655.

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Selenoproteins are unique proteins in which selenocysteine is inserted into the polypeptide chain by highly specialized translational machinery. They exist within all three kingdoms of life. The functions of these proteins in biology are still being defined. In particular, the importance of selenoproteins in pathogenic microorganisms has received little attention. We first established that a nosocomial pathogen, Clostridium difficile, utilizes a selenoenzyme dependent pathway for energy metabolism. Following this initial characterization, we demonstrate that this pathway is linked to production of toxins by this organism. Finally, we show that interruption of selenium metabolism is a viable pathway for development of antimicrobials against this, and other selenoprotein dependent pathogens. We investigated whether Stickland reactions (paired amino acid fermentation) might be at the heart of C. difficile's bioenergetic pathways. Growth of C. difficile on Stickland pairs yielded large increases in cell density in a limiting basal medium, demonstrating these reactions are tied to ATP production. Selenium supplementation was required for this increase in cell yield. Analysis of genome sequence data reveals genes encoding the protein components of two key selenoenzyme reductases; glycine and D-proline reductase. These selenoenzymes were expressed upon addition of the corresponding Stickland acceptor (glycine, proline or hydroxyproline). Purification of the selenoenzyme D-proline reductase revealed a mixed complex of PrdA and PrdB (SeCys containing) proteins. D-proline reductase utilized only D-proline but not L-hydroxyproline, even in the presence of an expressed and purified proline racemase. The enzyme was found to be independent of divalent cations, and zinc was a potent inhibitor. These results show that Stickland reactions are key to the growth of C. difficile and that the mechanism of D-proline reductase may differ significantly from similar enzymes from non-pathogenic species. C. difficile pathogenesis is due to the production of toxins, A and B, members of the large clostridial cytotoxin family. Previous studies have shown that toxin production by this organism is influenced by the composition of the growth medium. We examined the impact of Stickland acceptor amino acids (Stickland acceptors; glycine, proline and hydroxyproline) on growth kinetics and yield, protein synthesis, toxin production and gene expression. Although addition of Stickland acceptors moderately increases growth yield and total protein synthesis, there does not appear to be a clear impact on entry into stationary phase. Glycine dramatically increases the amount of toxin released into the growth medium. Conversely, the addition of hydroxyproline suppresses toxin production. We examine possible mechanisms of regulation and demonstrate that CodY, a regulator of toxin gene transcription does not appear to mediate this effect. Given the importance of selenium dependent Stickland reactions to C. difficile growth and toxin production we aimed to examine the efficacy of blocking such pathways as a means of antimicrobial development. Selenide is the only known substrate for selenophosphate synthetase, the first enzyme involved in the specific incorporation of selenium into selenoproteins. We have identified a stable complex formed upon reaction of auranofin (a gold containing drug) with selenide in vitro. Auranofin potently inhibits the growth of C. difficile but does not similarly affect other clostridia that do not utilize selenoproteins to obtain energy. Moreover, auranofin inhibits the incorporation of radioisotope selenium (75Se) in selenoproteins in both E. coli, the prokaryotic model for selenoprotein synthesis, and C. difficile without impacting total protein synthesis. Auranofin blocks the uptake of selenium and results in the accumulation of the auranofin-selenide adduct in the culture medium. Addition of selenium in the form of selenite or L-selenocysteine to the growth media significantly reduces the inhibitory action of auranofin on the growth of C. difficile. Based on these results, we propose that formation of this complex and the subsequent deficiency in available selenium for selenoprotein synthesis is the mechanism by which auranofin inhibits C. difficile growth. The antimicrobial potential of blocking selenium metabolism is further demonstrated in the dental pathogen Treponema denticola. We show that auranofin blocks the growth this organism which also participates in Stickland fermentation. In addition, we provide evidence that the antimicrobial action of stannous salts against T. denticola is also mediated through inhibition of the metabolism of selenium. These studies clearly show that, at least in a subset of microbes that use selenium for the synthesis of selenoproteins, the need for this metalloid can be a useful target for future antimicrobial development.
Ph.D.
Department of Biomolecular Science
Burnett College of Biomedical Sciences
Biomedical Sciences PhD

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20

Edwards, Kelly Katherine. "Bacterial factors contributing to the pathogenesis of the hemolytic uremic syndrome". MU has:, 2002. http://wwwlib.umi.com/cr/mo/fullcit?p3060096.

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21

Roberts, Daniel Paul. "Molecular mechanisms of pathogenesis incited by Erwinia carotovora subsp. carotovora". Diss., Virginia Polytechnic Institute and State University, 1985. http://hdl.handle.net/10919/71251.

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Erwinia carotovora subsp. Carotovora (Ecc) incites soft-rot on many plants. It is believed that soft-rot is due to the concerted activity of extracellular enzymes. Recombinant DNA techniques were used to study the molecular basis of pathogenesis incited by Ecc. Specifically, a clone library of Ecc strain EC14 DNA in plasmid pBR322 was constructed and transformed into Escherichia coli strain HB101. Some of the E. coli strains that contain these hybrid plasmids produce pectinases or cellulase(s). Plasmid pDR1 contains a 3.4 kilobase (kb) EC14 DNA fragment and mediates the production of endo-pectate lyases with isoelectric points (pI) of 9.5 and 7.5 in strain HB101. The pI 9.5 enzyme is believed to be the major extracellular pectolytic enzyme in soft-rot while the pI 7.5 enzyme has no documented counterpart in EC14. Subclone and transposon tn5 analyses of pDR1 indicate that 1.5 kb is necessary for the production of the pI 9.5 and pI 7.5 enzymes and that these enzymes are produced independently of other EC14 pectate lyase enzymes. Plasmid pDR30 contains a 2.1 kb EC14 DNA insert that mediates the production of an endo-polygalacturonase and an exo-pectate lyase in HB101. The exo-pectate lyase encoded by pDR30 produces an inducer of endo-pectate lyase synthesis as a reaction product. The endo-polygalacturonase encoded by pDR30 is thought to play a role in plant cell wall pectic polymer degradation. Restriction endonuclease and Southern hybrididizatian analyses indicate that the EC14 genes on plasmids pDR1 and pDR30 are not part of the same operon. Escherichia coli strain HB101 containing plasmid pDR1 or plasmid pDR30 is unable to macerate potato tuber slices. However, HB101 containing plasmids pDR1 and pDR30 can cause limited maceration of potato tuber slices. There appears to be a genetic interaction between plasmids pDR1 and pDR30 in maceration of potato tuber tissue. However, the EC14 gene(s) contained on plasmid pDR1 are transcribed independently of the EC14 genes contained on plasmid pDR30. It is possible that transcription of certain pectolytic enzymes independent of other pectolytic enzymes provides a flexible system for plant cell wall pectic polymer degradation.
Ph. D.

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22

Leiby, Nicholas. "Adaptation and Specialization in the Evolution of Bacterial Metabolism". Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11364.

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Specialization is a balance of evolutionary adaptation and its accompanying costs. Here we focus on the Lenski Long-Term Evolution Experiment, which has maintained cultures of Escherichia coli in the same, defined seasonal environment for 50,000 generations. This dissertation explores the extent and means by which metabolic specialization occurs over an extended period in the same environment.

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23

Funk, Michael A. (Michael Andrew). "Structural studies of radical enzymes in bacterial central metabolism". Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98816.

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Thesis: Ph. D. in Biological Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2015.
Vita. Cataloged from PDF version of thesis.
Includes bibliographical references.
Anaerobic bacteria play a crucial role in cycling of nutrients in diverse ecosystems, degradation of organic compounds, and as key members of the human gut microbiome. The absence of oxygen limits the chemistry that bacteria can perform; however, these organisms do make use of organic radical cofactors that are oxygen sensitive. This thesis presents a structural analysis of three enzymes that utilize a glycyl radical cofactor to perform difficult, radical-based chemistry. Benzylsuccinate synthase catalyzes the first step in the anaerobic degradation of toluene, a major component of gasoline and an environmental pollutant. Choline trimethylamine-lyase is used by gut bacteria to degrade choline, producing a byproduct, trimethylamine, which is linked to human diseases. These two enzymes share a common protein fold and also utilize a similar series of steps to initiate chemistry on their substrates. However, once they have generated a radical intermediate, the enzyme active site guides very different chemical steps in these two enzymes. Class III ribonucleotide reductases catalyze the same chemical reaction as observed in aerobic or oxygen independent systems, but utilize a glycyl radical cofactor to initiate chemistry. X-ray crystal structures have given us snapshots of these enzymes in action and accompanying biochemical experiments are help reveal the mechanisms they use to control radical chemistry. These structures have highlighted the potential diversity of chemical reactions available to anaerobic organisms through the use of a conserved enzyme fold.
by Michael A. Funk.
Ph. D. in Biological Chemistry

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24

Gohil, Amit. "Bacterial oxidoreductase-catalysed metabolism of phenol and aniline substrates". Thesis, Queen's University Belfast, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706684.

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Chapter 1. Provides an Introduction to dioxygenases, their Involvement In aromatic degradation ant formation of chiral c/s-dlols. The toluene dioxygenase (TOO, mechanism of action, amino acids In the active site and their blocatalytlc activity towards phenolic metabolites are Introduced. Application: of these chiral c/s-dlol metabolites obtained by TDO-catalysed oxidations are exemplified. Chapter 2. Whole cell biotransformations of meta-methoxyphenol using the constitutive mutanl Pseudomonas putlda UV4 strain expressing TOO and Inducer recombinant Escherichia coll (pCL-4T strain exclusively expressing TDO was conducted. Scale-up blotransformatlon of meta methoxyphenol was also discussed. The metabolites were Isolated and characterised fully by uslnf X-ray crystallography, NMR spectroscopy, GC- and LC- mass spectrometry. Add- and base chemocatalysed reactions of the major cydohexenone c/s-dlol metabolites were also studied. Chapter 3. Similar methods were used for the blotransformatlon of ort/io-methoxyphenol (gualacol, using P. putlda UV4 and Escherichia coll (pCL-4T) strains, where the metabolites were Isolated and characterised fully. In-depth stability, conformational and configurational studies were conducted on the isolated metabolites. Results for blotransformatlon of para-methoxyphenol were also presented. Biosynthetic pathways were proposed and discussed, for the formation of novel chiral metabolites derived from phenolic substrates. Chapter 4. Having established the structure and stereochemistry of metabolites derived from methoxyphenols (Chapter 2 and 3), studies of whole cell blotransformatlons with a series of substituted anilines and their corresponding phenol counterparts using P. putlda UV4 and E.coll (pCL-4T) whole cells were described. Blotransformatlon of a series of other substituted phenols, catechols and hydroquinones using both these strains were also attempted. Detection and confirmation of the presence of TDO-catalysed metabolites was examined by a combination of GC-MS and LC-MS analytical methods. Chapter 5. Contains prellmarary computational docking studies and elaborates on the future prospects of dioxygenase-catalysed studies. Chapter 6. Methodology, experimental and computational docking results.

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25

Rogers, Sarah Victoria. "The biosynthesis of some bacterial and fungal polyketide metabolites". Thesis, Durham University, 1994. http://etheses.dur.ac.uk/5112/.

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Methylmalonyl-CoA is a key building block in the biosynthesis of propionate derived polyketide metabolites. There are several known metabolic sources of methylmalonyl-CoA, e.g. succinyl-CoA (citric acid cycle), valine and isoleudne. An objective of this research was to investigate the role of the DNA base, thymine, as a source of methyhnalonyl-CoA in Streptomyces and hence probe the link between primary and secondary metabolism. Feeding key intermediates of the thymine and valine cataboHc pathways, i.e. [(^13)C(^2)H(_3)-methyl]-thymine, [(^13)C-methyl]- and [l-(613)c]-β- aminoisobutyric acid, sodium [3-(^13)C]-isobutyrate, sodium [(^13)C-methyl]- methacrylate and sodium [l-(^13)C]-methacrylate, to the monensin A producer, Streptomyces cinnamonensis, provided evidence of the reductive catabolism of thymine occurring in Streptomyces, analogous to mammals. The results also provided evidence which supports the existence of a novel deaminase enzyme mediating the transformation of β-aminoisobutyric add and methacrylyl-CoA. Cubensic add, isolated from Xylaria cubensis, is a long chain fungal metabolite possessing eight pendant methyl groups. Its biosynthesis from acetate and L-methionine units was demonstrated with the aid of feeding experiments, proving a classical fungal mode of assembly. Attempts to incorporate an advanced methylated precursor into cubensic add were unsuccessful. Biological intramolecular Diels-Alder reactions are implicated in the biosynthesis of a wide range of polyketide metabolites, e.g. nargenicin, solanapyrones. Attempts to demonstrate, by feeding an isotopically labelled precursor, an intramolecular Diels-Alder mechanism for the formation of the sbc membered ring in cytochalasin D, proved inconclusive. In the event, the precursor was degraded to acetate. This degradation was suppressed in the second attempt by the addition of a β-oxidation inhibitor, but still no incorporation of labelled precursor was evident.

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26

Ward, Philip Nicholas. "Characterisation of an essential c-terminal region of the Pasteurella multiocida toxin". Thesis, University of Hertfordshire, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245402.

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Curtis, Richard Nigel. "The role of bacterial superantigen toxins in the pathogenesis of Kawasaki disease". Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299621.

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Russell, Brandon S. (Brandon Skylur). "Nucleic acid modifications in bacterial pathogens - impact on pathogenesis, diagnosis, and therapy". Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90151.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Nucleic acids are subject to extensive chemical modification by all organisms. These modifications display incredible structural diversity, and some are essential for survival. Intriguingly, several of these modifications are unique to bacteria, including many human pathogens. Given the enormous global disease burden due to bacterial infections, and the rapidly increasing rates of antibiotic resistance reported across the world, the need for research to address mechanisms of bacterial survival is more pressing than ever. The goal of this thesis was to determine the function of nucleic acid modifications in pathogenic bacteria, and to evaluate their impact on the three major stages of the infectious disease process: pathogenesis, diagnosis, and therapy. We first used quantitative profiling of tRNA modifications to identify novel stress responses that help mediate host invasion in the world's most common pathogen, Helicobacter pylori. This work uncovered potentially novel targets for the development of new compounds that inhibit pathogenesis. We then developed a new animal model of mycobacterial lung infection that enables drug development and biomarker screening studies in standard laboratories without high-containment facilities. We showed that infection with Mycobacterium bovis bacille Calmette-Guérin produces a granulomatous lung disease in rats that recapitulates many of the important pathological features of human tuberculosis. This model also allowed us to test the utility of nucleic acid modifications as diagnostic biomarkers. Finally, we investigated the effect of the common, transferable bacterial DNA modification phosphorothioation on oxidative and antibiotic stress responses in several pathogens. We showed that phosphorothioation can reduce the effectiveness of antibiotic therapy, which may make it an environmental source of acquired antibiotic resistance. These studies show that nucleic acid modifications play diverse roles in pathogenic bacteria, and that their modulation may be a promising target for developing new tools that can disrupt pathogenesis, improve diagnosis, and strengthen therapy.
by Brandon S. Russell.
Ph. D.

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29

Manoharan, B. "The use of transposon libraries to investigate the evolution of bacterial pathogenesis". Thesis, University of the West of England, Bristol, 2014. http://eprints.uwe.ac.uk/22349/.

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Pseudomonas syringae pathovar phaseolicola (Pph) is the seed borne causative agent of halo blight disease in the common bean, Phaseolus vulgaris. Gene-for-gene interactions are widespread and a very important aspect of plant disease resistance. Pph race 6 strain 1448A contains no known avirulence genes and can cause disease on all bean cultivars in the differential series; however, Pph race 4 strain 1302A contains the avirulence gene avrPphB, and causes a rapid hypersensitive response (HR) in bean cultivar Tendergreen. Screening transposon (Tn) mutant libraries may allow discovery of many known and novel genes necessary for many characteristics such as adaptations to the environment, to colonise and to cause disease. Two random Tn mutant libraries, Pph 1302A::Tn and Pph 1448A::Tn were created using Tn IS-Ω-Km/hah. Pph mutants were successfully produced using the optimized conditions. A total of 960 mutants in Pph strains 1302A and 1448A were tested for their phenotypic characterisation and for identification of genome mobility in Pph 1302A and competence genes in Pph 1448A. To investigate genes involved in Pph colonisation of plants and evolution of Pph pathogenesis by HGT, the Tn mutant libraries were screened for changes in bacterial phenotypic characteristics such as colony morphology, motility, biofilm formation, growth rate in bean apoplastic fluid and conjugation. Selected mutants were assessed for in vitro and in planta growth rate and pathogenicity. Results showed that number of Pph mutants with different phenotypes caused restriction of growth in plants and/or reduced symptoms. In colony morphology screening, 28 small (11 Pph 1302A and 17 Pph 1448A) and 29 big (four Pph 1302A and 25 Pph 1448A) colony variant mutants were obtained. Eight Pph mutants showed highly reduced colony size and were also affected in both swarming and swimming motility. One very small colony mutant had a Tn insertion in the gene for HdtS protein which is involved in quorum sensing of bacteria. Among 29 big colony mutants, a Tn insertion in the gene for outer membrane protein A (OmpA) affected colony morphology, motility and highly impaired in planta growth and pathogenicity symptoms. Other phenotypic screening methods included motility tests, where several Pph mutants showed highly reduced swarming and swimming motility. Six Pph 1302A::Tn mutants showed some reduction in biofilm formation/attachment. Three Pph 1302A::Tn mutants had a higher growth rate in minimal media supplemented with apoplastic fluid. Two Pph 1448A::Tn mutants showed significantly reduced growth rate in vitro in Luria Bertani liquid media. Finally, eight Pph 1448A::Tn mutants showed complete absence of disease in bean pods. These results demonstrate the identification of many genes involved in key bacterial behaviour and are important for plant colonisation and therefore disease in bean plants. Screening for genome mobility by Pph 1302A::Tn mutant library showed three Pph 1302A::Tn mutants which may have the ability to transfer from Pph 1302A to Pph 1448A. These mutations were in areas of the genome associated with antibiotic resistance and genes for the Omp family, mobile genetic elements and type III effector protein and conserved hypothetical and adhesion protein. All three mutants may be involved in HGT and contribute to the evolution of Pph pathogenesis. Thirty five Pseudomonas strains were examined for their conjugation and transformation ability. Results showed two Pph strains Pph 882 (race 2) and Pph 1375A (race 5) have transformation ability and 28 Pseudomonas strains have conjugation ability. However, during this study transformation ability of Pph 1448A appeared to be lost. Examination of the loss of competence in Pph 1448A showed two changes i.e. growth rate reduction in vitro in LB liquid media and plasmid genome alteration by bean pod passage. Plants and bacteria can interact with one another in a variety of different ways. The interaction may be beneficial, harmful or neutral for the plant. This work has contributed to the understanding of these interactions between Pph 1302A and Pph 1448A in their host plants. These may allow subsequent development of sustainable disease control strategies.

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McLaughlin, Simon D. "Clinical and laboratory studies of the bacterial pathogenesis and management of pouchitis". Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/5713.

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20-50% of patients develop pouchitis following restorative proctocolectomy for ulcerative colitis (UC). Pre-pouch ileitis (PPI) also develops in some of these patients. Bacteria are implicated in the pathogenesis of pouchitis and antibiotics are the mainstay of treatment. Studies were performed to examine the role of bacteria in the pathogenesis of this disease and to develop new treatment. Further studies examined the prevalence and implications of PPI and the efficacy and complications associated with maintenance antibiotic therapy. 16s rRNA sequencing demonstrated an increase in Proteobacteria and a reduction in Bacteroidetes in the UC compared with the familial adenomatous polyposis (FAP) cohort, but only limited differences between the UC non-pouchitis and pouchitis groups. We were unable to identify an individual species or phylotype specifically associated with pouchitis. Treatment with elemental diet produced a symptomatic improvement in 71% of chronic pouchitis patients but none entered clinical remission. Patients with PPI were identified, the prevalence, symptoms and short term outcomes of this group were studied. PPI was identified in 5.7% of patients with UC. All patients had associated pouchitis but not all were symptomatic. PPI was not associated with reclassification to Crohn’s disease. A subgroup of patients with symptomatic pre-pouch ileitis were treated with combination antibiotic therapy and 86% entered remission. Faecal samples from patients with antibiotic resistant pouchitis were grown on agar and sensitivity patterns identified. Following guided antibiotic therapy 80% of patients entered remission. Stool analysis also identified the presence of extended spectrum beta-lactamase (ESBL) resistant coliforms in 35% of patients with chronic pouchitis. Not all were symptomatic. PPI was associated with an increased risk of ESBL. Patients treated with maintenance antibiotic therapy were identified. Pre-pouch ileitis was associated with an increased risk of relapse. Reported side effects were rare and treatment was associated with an improved quality of life.

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31

Clough, Richard R. "The role of energy metabolism in the pathogenesis of Alzheimer's disease". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0004/MQ45034.pdf.

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Lisanby, Mark W. "Examination of the capacity of cathelicidins to control Bacillus anthracis pathogenesis". Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009p/lisanby.pdf.

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33

Oonthonpan, Lalita. "Two human Mitochondrial Pyruvate Carrier mutations reveal distinct mechanisms of molecular pathogenesis". Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/7006.

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The Mitochondrial Pyruvate Carrier (MPC) occupies a central metabolic node by transporting cytosolic pyruvate into the mitochondrial matrix, thereby linking glycolysis with mitochondrial metabolism. Two reported human MPC1 mutations cause developmental abnormalities, neurological problems, metabolic deficits, and for one patient, early death. We aimed to understand biochemical mechanisms by which the human patient c.C289T and c.T236A MPC1 alleles disrupt MPC function. MPC1 c.C289T encodes two protein variants, a mis-spliced, truncation mutant (A58G) and full-length point mutant (R97W). MPC1 c.T236A encodes a full-length point mutant (L79H). Using human patient fibroblasts and complementation of CRISPR-deleted, MPC1 null mouse C2C12 cells, we investigated how MPC1 mutations cause MPC deficiency. Truncated MPC1 A58G protein was intrinsically unstable and failed to form MPC complexes. The MPC1 R97W protein was less stable but when overexpressed formed complexes with MPC2 that retained pyruvate transport activity. Conversely, MPC1 L79H protein formed stable complexes with MPC2, but these complexes failed to transport pyruvate. These findings inform MPC structure-function relationships and delineate three distinct biochemical pathologies resulting from human patient MPC1 mutations and inform fundamental MPC structure-function relationships. These results also demonstrate an efficient molecular genetic system using the mouse C2C12 cell line to mechanistically investigate human inborn errors in pyruvate metabolism.

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34

Alday-Sanz, Victoria. "Studies on the pathogenesis of Vibrio spp infection in Penaeus monodon Fabricius". Thesis, University of Stirling, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261671.

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35

Auger, Graham Anthony. "Genetic manipulation of bacterial metabolism by altering a global regulator". Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265798.

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36

Winkler, Jonathan Alexander. "Improving antibiotic activity by manipulating bacterial reactive oxygen species metabolism". Thesis, Boston University, 2012. https://hdl.handle.net/2144/12675.

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Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
The discovery of antibiotics was one of the most important medical breakthroughs of the twentieth century, having a broad impact on overall life expectancy and public health. Unfortunately, antibiotic discovery has slowed significantly in recent times and has failed to match the rising incidence of antibiotic-resistant pathogens. Gram-negative pathogens are a particularly troublesome threat, primarily because these bacteria possess an outer membrane that prevents many antibiotics from accessing their primary cellular targets. While the discovery of novel antibiotics could help to address these issues, alternative strategies, such as improving the activity of preexisting antibiotics, are also needed. Bactericidal antibiotics have recently been shown to share a common mechanism of cell death, despite having different primary, cellular targets. This shared mechanism involves the metabolic production of reactive oxygen species (ROS), which can damage proteins, lipids, and nucleic acids, and can ultimately result in bacterial cell death. The body of work described here shows that this common mechanism can be exploited to improve antibiotic activity, regardless of the antibiotic's primary mode of action. First, I will describe how bacterial metabolism can be predictably perturbed to increase endogenous ROS production, and that increasing endogenous ROS is sufficient to enhance bacterial sensitivity to treatments with ROS-generating biocides, antibiotics, and immune cell attack. I will then describe work indicating that an ancient antimicrobial agent, silver salts, can also increase endogenous ROS production and potentiate the activity of multiple antibiotic classes. Furthermore, I show that silver salts can increase the outer membrane permeability of a Gram-negative organism. This property is exploited to enable vancomycin, an antibiotic that is specific for Gram-positive bacteria, to work against a Gram-negative organism. Together, this body of work demonstrates that bacterial ROS metabolism can be exploited effectively to enhance. antibiotic activity, which ultimately could result in the discovery and development of novel antimicrobial agents.

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37

Keerthisingam, Carmel Beulin. "Role of prostaglandin Eâ‚‚ in the pathogenesis of pulmonary fibrosis". Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325631.

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38

Thalme, Anders. "Infectious endocarditis, aspects on pathogenesis, diagnosis and prognosis /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-361-2/.

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39

Purdy, Shona Thomson. "The biochemistry and genetics of sorbitol metabolism in clostridium pasteurianum". Thesis, Heriot-Watt University, 1991. http://hdl.handle.net/10399/870.

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40

Bröms, Jeanette. "Type III secretion- the various functions of the translocon operon in bacterial pathogenesis". Doctoral thesis, Umeå University, Molecular Biology, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-331.

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In order to establish colonisation of a human host, pathogenic Yersinia use a type III protein secretion system to directly intoxicate host immune cells. Activation of this system requires target cell contact and is a highly regulated process. Both the intoxication and regulation events depend on the lcrGVHyopBD translocon operon, which is highly conserved in many bacterial pathogens. In this study, the role of individual operon members was analysed and functional domains identified by using the highly homologous pcrGVHpopBD operon of P. aeruginosa as a comparative tool.

Yersinia spp. and P. aeruginosa were shown to form translocation pores of a similar size that promoted equally efficient protein delivery. A strong dependency on interactions between native translocator(s) in protein delivery was revealed, suggesting that each pathogen has delicately fine-tuned this process to suit its own infection niche. In particular, the C-terminus of YopD was shown to possess functional specificity for effector delivery in Yersinia that could not be conferred by the comparable region in homologous PopD. Moreover, a role for LcrV and PcrV in substrate recognition during the protein delivery process was excluded.

The N-terminus of LcrH was recognized as a unique regulatory domain, mediating formation of LcrH-YscY regulatory complexes in Yersinia, while equivalent complexes with analogous proteins were not formed in P. aeruginosa. These results compliment the idea that a negative regulatory pathway involving LcrH, YopD, LcrQ and YscY is unique to Yersinia.

Finally, PcrH was identified as a new member of the translocator class of chaperones, being essential for assembly of a functional PopB/PopD mediated translocon in P. aeruginosa. However, in contrast to the other members of this family, PcrH was dispensable for type III regulation. Moreover, both LcrH and PcrH were shown to possess tetratricopeptide repeats crucial for their chaperone function. One tetratricopeptide repeat mutant in LcrH was even isolated that failed to secrete both YopB and YopD substrates, even though stability was maintained. This demonstrates for the first time that LcrH has a role in substrate secretion in addition to its critical role in promoting substrate stability.

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Sze, Marc Alexander. "The bacterial lung tissue microbiome in the pathogenesis of chronic obstructive pulmonary disease". Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54530.

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Rationale: Several laboratories have shown that the decline in lung function in Chronic Obstructive Pulmonary Disease (COPD) is associated with increased formation of tertiary lymphoid follicles. This provides direct histological evidence in support of the hypothesis that the decline in lung function is associated with activation of an adaptive immune response. The antigens responsible for driving this immune activation remain poorly understood. The recent realization that the human lung contains a bacterial microbiome that changes in association with the presence of COPD suggests the hypothesis that bacteria arising from within this microbiome might be responsible for activating the adaptive immune response in COPD. Approach: The research described in this thesis examines the lung tissue bacterial microbiome from patients with mild to moderate COPD as well as patients with very severe COPD. The bacterial microbiome from these studies utilized either nested or touchdown PCR followed by 454™ pyrotag sequencing of specific variable regions on the 16S rRNA gene. Changes in the microbiome were examined in relation to histological estimates of emphysematous destruction of the lung and inflammatory immune cell infiltration associated with this tissue remodeling process. Finally, Haemophilus influenzae, a bacterium identified from this microbiome, known to cause inflammation was compared to the host tissue repair process. Results: The different bacterial community was present in control and mild (GOLD 1) compared to moderate (GOLD 2) COPD. The community composition was also different between donor lung tissue and very severe (GOLD 4) COPD. Further, the analysis identified a list of 10 OTUs that discriminated between lung tissue affected by GOLD 4 COPD and controls. In addition, the data presented here indicate that the host immune response to these organisms precedes the structural changes associated with COPD. Conclusion: Collectively, these data confirm that there is a small but diverse microbiome in the normal human lung that becomes less diverse in COPD. Furthermore, the disappearance/appearance of certain OTUs can discriminate between control and COPD affected lung tissue and that some of these OTUs are associated with the inflammatory immune cell infiltration and tissue destruction that occurs in COPD.
Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate

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42

Bröms, Jeanette. "Type III secretion- the various functions of the translocon operon in bacterial pathogenesis /". Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-331.

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Kumar, Prashant. "CyclicAMP-PKA signaling in pathogen host interplay role in pathogenesis and bacterial invasion". Berlin mbv, 2009. http://d-nb.info/998089265/04.

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Cowie, Danielle. "Iron and Tuberculosis pathogenesis". Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86566.

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Thesis (MSc)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Iron is an essential element that plays a role in the process of respiration, oxygen transport and as a principle cofactor to several enzymes. Iron homeostasis is a finely regulated process since excess levels become toxic to healthy cells via the production of reactive oxygen species. A plethora of genes that control several key points throughout this regulatory process have been identified. Research focusing on changes in expression levels and downstream functional effects of these genes has become increasingly important over the past decade. One area of particular interest has emerged since a link between iron status and host response to Mycobacterium tuberculosis infection was discovered. Although the prevalence of Tuberculosis has decreased across the globe with the exception of Africa and parts of Europe, the mortality rate remains high. Therefore, research that focuses on understanding an individual’s predetermined susceptibility to TB infection at the genetic level could provide health care practitioners with the tools required to identify and educate at-risk individuals prior to TB infection. RT-qPCR was utilised to determine expression profiles for eight iron genes (CP, CYBRD1, FTH, FTL, LTF, HFE, HMOX1, and SCL40A1) normalised to three reference genes (ACTB, GUSB, and RPL37A1). Up-regulation is demonstrated in the TB group for transcript levels recorded for CYBRD1, HFE, HMOX1, and SLC40A1. Several measured serum parameters including conjugated, unconjugated, total bilirubin, and total protein were increased in the TB group while albumin was significantly lower in this group. Correlation analysis demonstrated that a positive correlation exists between transferrin saturation and iron and a negative correlation exists between transferrin and ferritin levels. Individuals categorised with low serum iron levels demonstrated lower CP/GUSB levels and higher HMOX1/GUSB levels. Individuals categorised with low transferrin saturation levels demonstrated higher FTL/GUSB and SLC40A1/GUSB levels and lower CP/GUSB. Results from this study provide further evidence for the relationship between iron status and TB infection rates, although protein studies are required to confirm these results. The data obtained illustrate the important role that these profiles and iron parameters may play in the clinical field when identifying at-risk individuals. Further investigation that focuses on which gene profile and parameter combinations show the most distinctive utility in the clinical setting is warranted.
AFRIKAANSE OPSOMMING: Yster is ‘n noodsaaklike element wat ‘n rol speel in die proses van respirasie en die vervoer van suurstof en ook ‘n belangrike ko-faktor vir verskeie ensieme is. Yster homeostase is op ‘n fyn manier gereguleer omdat oormatige vlakke toksies kan wees vir gesonde selle wanneer reaktiewe suurstofspesies geproduseer word. ‘n Magdom gene wat verskeie sleutelpunte in hierdie proses kontroleer is voorheen identifiseer. Navorsing wat fokus op die veranderinge in geenuitdrukkingsvlakke en die funksionele gevolge daarvan het oor die afgelope dekade toenemend belangrik geword. Een gebied van spesifieke belang het na vore gekom nadat ‘n verband tussen ystervlakke en die manier waarop die immuunstelsel reageer op Mycobacterium tuberculosis infeksie, ontdek is. Alhoewel die voorkoms van Tuberkulose wêreldwyd, behalwe in Afrika en sekere dele van Europa, afgeneem het, bly die sterftesyfer hoog. Daarom kan navorsing wat daarop fokus om ‘n individu se voorafbepaalde vatbaarheid vir TB-infeksie op die genetiese vlak te verstaan dalk aan gesondheidswerkers die regte instrumente verskaf om hoë-risiko individue te identifiseer en op te voed voordat hulle TB ontwikkel. RT-qPKR is gebruik om die geenuitdrukkingsvlakke van agt ystergene, wat met drie verwysings-gene (ACTB, GUSB, en RPL37A1) genormaliseer is, te bepaal. ‘n Toename in die uitdrukkingsvlakke van CYBRD1, HFE, HMOX1, en SLC40A1 is in die TB-groep waargeneem. Die bloedvlakke van verskeie parameters insluitend gekonjugeerde, ongekonjugeerde, totale bilirubin, en totale proteïen was hoër in die TB-groep, terwyl albuminvlakke laer was in hierdie groep. Korrelasie-analise het ‘n positiewe korrelasie tussen transferrin-versadiging en yster getoon, terwyl daar ‘n negatiewe korrelasie tussen transferrin- en ferritinvlakke gevind is. Individue met lae ystervlakke het laer CP/GUSB-vlakke en hoër HMOX1/GUSB-vlakke getoon. Individue met lae transferrin-versadiging het hoër FTL/GUSB- en SLC40A1/GUSB-vlakke en laer CP/GUSB-vlakke getoon. Resultate uit hierdie studie verskaf verdere getuienis dat daar ‘n verwantskap tussen ystervlakke en TB-infeksiekoerse bestaan, alhoewel proteïenstudies nodig is om hierdie resultate te bevestig. Die data dui op die belangrike rol wat hierdie profiele en ystervlakke in die kliniese veld mag speel in die identifisering van hoë-risiko individue. Verdere ondersoek, gefokus op watter geenprofiel en parameterkombinasies die grootste nut in die kliniese omgewing bied, is geregverdig.

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Bian, Zhao. "Nucleator-driven assembly of curli organelles and their pathophysiological role in E. coli septic shock /". Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3688-9/.

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Dunstan, R. H. "A GC-MS approach to carbon and nitrogen metabolism in Paracoccus denitrificans". Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370248.

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Oberbeck, Nina. "The role of intrauterine aldehyde catabolism in the pathogenesis of Fanconi anaemia". Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708527.

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Ismaili, Arif. "Signal transduction and cytoskeletal responses in the pathogenesis of attaching and effacing bacterial infection". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ33906.pdf.

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Scott, Euan. "Probing the bacterial pathogenesis of ESKAPE species utilising C. elegans as a model system". Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/422278/.

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The nematode C. elegans is widely used as a model organism throughout biology, including as a host for bacterial infections. C. elegans can be exposed to a range of bacterial strains through presentation of bacteria as potential food sources in the form of a lawn on agar plates and can subsequently be observed. This thesis specifically examined strains from three Gram-negative species of the ESKAPE group, a group of troublesome antibiotic resistant and pathogenic bacterial pathogens. A range of strains from the Gram-negative ESKAPE species Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa were examined in C. elegans, and compared against E. coli OP50, the standard laboratory food source of the animal as a control. This allows similarities and differences between different bacterial strains to be identified as to how they affect C. elegans biology. C. elegans populations on lawns of OP50 show a progressive increase in leaving the bacterial lawn after extended exposure. This enhanced food-leaving was determined to be driven by C. elegans larvae that are produced by adult animals on the bacterial lawn. This was dependent on a homologue of the mammalian hormone oxytocin and indicates that this behaviour is related to signalling that controls parental behaviours in mammals. When C. elegans populations were examined on lawns of ESKAPE bacteria, some bacterial strains significantly reduced C. elegans lifespan, indicating pathogenicity, with different degrees of virulence being observed. In addition, individual pathogenic bacterial strains were found to generate a food aversion response in C. elegans, a previously reported indicator of bacterial pathogenicity. Further investigation revealed that neither colonisation nor the subsequent clearance of bacteria from the C. elegans intestine underpins the differential pathogenicity of these bacterial strains. Further analysis showed that neuropeptides are key modulators of the process of colonisation and act in both pathogenic and benign bacteria. Analysis of the food aversion provoked by pathogenic bacteria revealed that signalling by biogenic amines acts to modulate this behaviour. Specifically, serotonin acts to promote the food aversion response and octopamine acts to supress food aversion to specific pathogenic strains. From undertaking all these investigations, it can be seen that individual bacterial strains can exert diverse biological effects on C. elegans as a model host, and the comparative approach taken in this thesis allows insight to be made about individual and diverse bacterial strains. The result in this thesis provide further avenues for investigation as to how bacterial pathogenesis is mediated in C. elegans as a model host organism, specifically in terms of virulence factors present in different bacterial strains and further neural controls of the C. elegans biological response to bacteria.

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Darby, Creg Burns. "Paralysis of Caenorhabditis elegans by Pseudomonas aeruginosa : a genetically tractable model for bacterial pathogenesis /". Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/10304.

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