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dc.contributor.advisorJayaraman, Arul
dc.creatorKohli, Nandita
dc.date.accessioned2017-08-21T14:42:59Z
dc.date.available2019-05-01T06:06:57Z
dc.date.created2017-05
dc.date.issued2017-05-05
dc.date.submittedMay 2017
dc.identifier.urihttps://hdl.handle.net/1969.1/161570
dc.description.abstractThe microbial community present in the gastrointestinal tract is an important component of the host defense against pathogen infections. Prior work from our lab demonstrated that indole, a microbial metabolite of tryptophan, reduces enterohemorrhagic Escherichia coli O157:H7 attachment to intestinal epithelial cells and biofilm formation, suggesting that indole may be an effector/attenuator of colonization for a number of enteric pathogens. Here, we show that indole attenuates Salmonella Typhimurium (Salmonella) virulence and invasion as well as increases resistance of host cells to Salmonella invasion. Indole-exposed Salmonella colonized mice less effectively compared to solvent-treated controls, as evident by competitive index values less than 1 in multiple organs. Indole-exposed Salmonella demonstrated 160-fold less invasion of HeLa epithelial cells and 2-fold less invasion of J774A.1 macrophages, compared to solvent-treated controls. However, indole did not affect Salmonella intracellular survival in J774A.1 macrophages, suggesting that indole primarily affects Salmonella invasion. The decrease in invasion was corroborated by a decrease in expression of multiple Salmonella Pathogenicity Island-1 (SPI-1) genes. Indole also reduced Salmonella motility and acts as a chemo-repellent through the Tsr chemoreceptor. We also identified that the effect of indole on Salmonella virulence was mediated by both PhoPQ-dependent and independent mechanisms. Further investigation of PhoPQ-dependent mechanism using Autodock Vina, Molecular Dynamic simulations and in vitro mutagenesis experiments revealed that indole does not bind to the periplasmic domain of PhoQ. Computational analysis predicted indole-binding to the cytoplasmic catalytic domain. Indole also synergistically enhanced the inhibitory effect of a short chain fatty acid cocktail on SPI-1 gene expression. Lastly, indole-treated HeLa cells were 70% more resistant to Salmonella invasion suggesting that indole also increases resistance of epithelial cells to colonization. Our results demonstrate that indole is an important microbiota metabolite that has direct anti-infective effects on Salmonella and host cells, revealing novel mechanisms of pathogen colonization resistance.en
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.subjectIndoleen
dc.subjectSalmonella virulenceen
dc.subjectmicrobiota metaboliteen
dc.subjectPhoPQen
dc.subjectchemorepellenten
dc.subjectTsren
dc.titleInvestigating Indole-Mediated Modulation of Salmonella Virulence and Chemotaxisen
dc.typeThesisen
thesis.degree.departmentChemical Engineeringen
thesis.degree.disciplineChemical Engineeringen
thesis.degree.grantorTexas A & M Universityen
thesis.degree.nameDoctor of Philosophyen
thesis.degree.levelDoctoralen
dc.contributor.committeeMemberAlaniz, Robert C
dc.contributor.committeeMemberKao, Katy
dc.contributor.committeeMemberChen, Zhilei
dc.type.materialtexten
dc.date.updated2017-08-21T14:42:59Z
local.embargo.terms2019-05-01
local.etdauthor.orcid0000-0001-9017-2188


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