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Chlamydia Subversion of Host Lipid Transport: Interactions with Cytoplasmic Lipid Droplets

dc.contributor.advisor Valdivia, Raphael H Cocchiaro, Jordan Lindsey 2009-05-01T18:37:23Z 2011-07-26T04:30:03Z 2009
dc.description.abstract <p>The <italic>Chlamydiaceae</italic> are Gram-negative, obligate intracellular bacteria that are significant pathogens of humans and animals. Intracellularly, the bacteria reside in a membrane-bound vacuole, called the inclusion, from which they manipulate host processes to create a niche optimal for survival and propagation. Acquisition of host-derived lipids is essential for chlamydial growth, yet the source of lipids and mechanisms of trafficking to the inclusion are not well-established. The inclusion avoids interaction with several classical membrane and lipid transport pathways. In a functional genomic screen to identify host modulating chlamydial proteins, our lab identified cytosolic lipid droplets (LDs) as potential target organelles of <italic>Chlamydia</italic>. LDs are postulated to function in many cellular processes, such as lipid metabolism and transport, membrane trafficking, and cell signaling; therefore, we hypothesized that LDs may be important for <italic>Chlamydia</italic> pathogenesis as a source of lipids or as a platform for regulating other cellular functions. Here, we characterize the interaction between eukaryotic LDs and the chlamydial inclusion.</p><p> We find that LDs are recruited to the <italic>Chlamydia</italic> inclusion, chlamydial infection disrupts neutral lipid homeostasis, and pharmacological prevention of LD formation inhibits chlamydial replication. <italic>Chlamydia</italic> produces proteins (Ldas) that localize with LDs in yeast and mammalian cells when transiently expressed and are exported out of the inclusion to peripheral lipid-rich structures during infection. By electron microscopy and live cell imaging, we observe the translocation of intact LDs into the <italic>Chlamydia</italic> inclusion lumen. Biochemical and microscopic analysis of LDs from infected cells reveals that LD translocation may occur at specialized subregions of the inclusion membrane. The <italic>Chlamydia</italic> Lda3 protein is implicated in LD tethering to the inclusion membrane, and displacement of the protective coat protein, ADRP, from LD surfaces. This phenomenon could provide access for lipases to the LD core for utilization by the replicating bacteria. Additionally, the functional domains of Lda3 involved in binding to LD and inclusion membranes are identified. </p><p> In these studies, we identify eukaryotic lipid droplets (LDs) as a novel target organelle important for <italic>Chlamydia</italic> pathogenesis and describe a unique mechanism of whole organelle sequestration not previously observed for bacterial pathogens. These results represent a fundamental shift in our understanding of host interactions with the chlamydial inclusion, and may represent a new area for research in the field of cellular microbiology.</p>
dc.format.extent 47052163 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Biology, Microbiology
dc.subject Biology, Cell
dc.subject Chlamydia
dc.subject inclusion membrane
dc.subject intralumenal
dc.subject Lda
dc.subject lipid droplets
dc.subject translocation
dc.title Chlamydia Subversion of Host Lipid Transport: Interactions with Cytoplasmic Lipid Droplets
dc.type Dissertation
dc.department Molecular Genetics and Microbiology
duke.embargo.months 24

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