Date of Award
Master of Science in Biomedical Sciences
Susan Hingley, PhD
Denah Appelt, PhD
Heather Montie, PhD
Background Alzheimer disease includes plaques consisting of aggregates of amyloid beta (Aβ). Aβ is the product of abnormal cleavage of amyloid precursor protein (APP) by the secretases β-APP cleaving enzyme-I (BACE1), Presenilin-1 (PSEN1) and disintegrin and metalloprotcinase-10 (ADAM10). Recent studies postulate a correlation between amyloidogenic processing of APP and infection of neuronal cells by bacteria or viruses. Here we examine the ability of Herpes simplex virus type I (HSV-1) and Chlamydia pneumoniae (Cpn) to modify the expression of BACE1, PSEN1, and ADAM10 in infected astrocytes. Knowing how these two pathogens might affect the neurodegenerative pathway to Aβ may give us insight into the etiology of Alzheimer disease.
Methods Astrocytes were infected in vitro with Cpn and/or HSV-1. At 24 and 48 hours of infection, the expression of ADAM10, BACE1 and PSEN1 was quantified by RT2-PCR. Data from singly or dually infected cells were compared to uninfected cells. Cpn and HSV-1 copy numbers were measured by qPCR from the same RNA samples. A potential effect of infection on Aβ processing was examined by immunofluorescent labeling of astrocytes.
Results After 24 hours of HSV-1 infection, cells had decreased expression of ADAM10, BACE1 & PSEN1, which was significantly more extensive after 48 hours of HSV-1 infection. In contrast, in cells infected with Cpn for 48 hours, BACE1 expression was significantly increased, whereas that of ADAM10 and PSEN1 was unchanged. Interestingly, concurrent infection with HSV-1 and Cpn lessened the reduction in gene expression due to HSV-1 alone. Cpn cDNA copy numbers were significantly increased in the presence of HSV-1. HSV-1 cDNA copy numbers were largely unchanged by the presence ofCpn, however, a decrease in HSV-1 cDNA copy number was detected if Cpn was added simultaneously with HSV-1. Immunofluorescent labeling revealed increased labeling of Aβ in infected astrocytes relative to uninfected cells.
Conclusions While HSV-1 infection may decrease host cell secretase gene expression, the presence of Cpn may modulate this effect. The ability of either pathogen alone to induce changes in the amyloidogenic pathway may be altered during active Cpn and HSV-1 coinfection.
Haque, Sidra Montaha, "Herpes Simplex Virus Type 1 and Chlamydia Pneumoniae Co-infection in Human Astrocytes Alter Host Cell Transcription of ADAM10, BACEL and PSEN1, Secretases Implicated in Alzheimer Disease" (2019). PCOM Biomedical Studies Student Scholarship. 169.