Infection of Neuronal Cells with HSV-1 Alters Expression of Genes Associated with Autophagy and Apoptosis: Possible Mechanisms of Alzheimer's Disease-like Neurodegeneration
Date of Award
Master of Science in Biomedical Sciences
Susan Hingly, PhD
Denah Apelt, PhD
Brian Balin, PhD
This study investigates the potential role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of neurodegenerative disorders, including Alzheimer’s Disease (AD) by exploring changes in gene expression related to antiviral immunity and the autophagic pathway. Autophagy is a process by which cellular organelles and proteins are recycled to create more energy for the cell and it can function as an innate immune response that degrades intracellular microorganisms. Dysregulation of autophagy has been linked to neurodegeneration, and HSV-1 has been shown to inhibit the induction as well as completion of autophagy, which would potentially contribute to cytopathology. Changes in gene expression in HSV-1-infected human neuronal SK-N-MC cells relative to uninfected cells were analyzed using RT2-PCR microarrays. Genes exhibiting greater than a 2.5-fold increase in mRNA levels upon infection with HSV-1 included genes encoding chemokine ligands (CXCL10, CXCL11, CXCL9) and various cytokines (IFNα2, IFNα4, IFNγ, IL1β, IL8, IL15 and TNF). Numerous genes associated with autophagy regulation (CASP8, CXCR4, FAS, PIK3CG), and autophagosome or autolysosome formation (ATG16L2, ATG9B, DRAM1, FAM176A) were also upregulated. Immunofluorescent labeling for lysosomal associated membrane protein-1 (LAMP-1) and protein 1 light chain 3 (LC3B), was used to evaluate changes in lysosome and autophagosome levels, respectively, following infection with HSV-1 or treatment with rapamycin (RM) or chloroquine (CQ), known activators of autophagy. The most obvious change in either infected or treated neuronal cells was an increase in labeling for LAMP-1 as compared to uninfected/untreated cells. No obvious colocalization of the autophagosome and lysosome markers was observed. Experimental data suggests that while autophagy initiation may occur, the complete execution of the process may be inhibited. Further analysis of the impact of HSV-1 on autophagy may suggest a mechanism by which HSV-1 can contribute to some of the pathological changes in neurons associated with neurodegeneration, such as that seen in AD.
Mark, Alexis M., "Infection of Neuronal Cells with HSV-1 Alters Expression of Genes Associated with Autophagy and Apoptosis: Possible Mechanisms of Alzheimer's Disease-like Neurodegeneration" (2012). PCOM Biomedical Studies Student Scholarship. 44.
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