Chlamydia pneumoniae Infection of Neuronal Cells Induces Changes in Calcium-Associated Gene Expression Consistent with Alzheimer's Disease

Date of Award

8-2013

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Denah M Appelt, PhD

Second Advisor

Brian J Balin, PhD

Third Advisor

Marcus Bell, PhD

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease in humans wherein the causative underlying mechanisms have not been discovered. Previous studies in our lab have shown that cells infected with the obligate intracellular bacterium Chlamydia pneumoniae (Cpn) exhibit altered gene expression consistent with that observed in AD. Furthermore, AD neurodegeneration has been linked to dysregulation of intracellular calcium and calcium-related processes. Therefore, we hypothesize that one mechanism by which pathogenesis evolves in AD is through infection-induced changes in calcium-related gene expression. Our objective was to determine if infection of neuronal cells with Cpn alters expression of calcium-related genes that play a role in neuronal functions such as learning, memory, neuronal synaptic function, and neurodegeneration that ultimately can be associated with AD pathogenesis. To test this hypothesis, neuronal cells were infected with Cpn (AR39, MOI=l) at four time points spanning from 3 to 72 hours. Chlamydia infection was validated for all time points by Real-Time Polymerase Chain Reaction (RT-PCR). Following infection, calcium-related genes were screened with real-time PCR microarrays. Approximately 64 of 84 genes displayed regulation changes of 2-fold or greater at a minimum of one time point, including calcium-responsive genes pertaining to neurotransmitters, cell cycle, growth factors, signaling, transcription, metabolism, and immune regulation. The majority of genes were initially up-regulated at the early 3 hour time point, then returned to baseline or below by the 72 hour time point Several of the affected genes have been directly or indirectly implicated in AD pathogenesis, or can be linked to neuronal deficits that are characteristic of AD. Additionally, protein expression of select genes in both uninfected and infected cells was detected via western analysis. In comparison to uninfected cells, protein expression changed in infected cells suggesting that infection leads to altered protein processing and/or expression. Our data suggest that Cpn alters calcium-related gene expression in host neurons consistent with calcium dysfunction previously documented in AD. This study may elucidate how, in its effort to establish a favorable environment, Cpn could affect gene transcription and/or cellular processes that contribute to AD pathogenesis.

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