Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medicine

Major Professor

Subhra Mohapatra, Ph.D.

Committee Member

Paula Bickford, Ph.D.

Committee Member

Alison Willing, Ph.D.

Committee Member

Jerome Breslin, Ph.D.

Committee Member

Andreas Seyfang, Ph.D.

Keywords

ACE2, Alzheimer's Disease, BBB, SARS-CoV-2, Transcytosis

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has provisional counts of over 110 million documented cases and 1.218 million deaths (as of February 2024) in the United States since January 2020. SARS-CoV-2 is an airborne respiratory virus that primarily infects the lungs via the ACE2 receptor but has well-documented secondary target organs including the kidneys, the gastrointestinal tract, the heart, and the skin. SARS-CoV-2 also infects the brain, but the hematogenous route of viral entry to brain is still not fully characterized. Understanding how SARS-CoV-2 traverses the blood-brain barrier (BBB) as well as how it affects the molecular functions of the BBB are unclear. In this study, we investigated the roles of the receptors angiotensin converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4) in SARS-CoV-2 infection of the discrete cellular components of a transwell BBB model comprising HUVECs, astrocytes, pericytes. Our results demonstrate that direct infection on the BBB model does not modulate paracellular permeability. Also, our results show that SARS-CoV-2 utilizes clathrin and caveolin-mediated endocytosis to traverse the BBB resulting in direct infection of the brain-side of the BBB model with minimal endothelial infection. In conclusion, the BBB is susceptible to SARS-CoV-2 infection in multiple ways including direct infection of endothelium, astrocytes, and pericytes involving ACE2 and/or DPP4 and the blood-to-brain transcytosis, which is a stochastic event that does not require the presence of host receptors.Up to 30% of individuals with mild to severe disease develop long COVID, exhibiting diverse neurologic symptoms including dementias. However, there is a paucity of knowledge of molecular brain markers and whether these can precipitate the onset of Alzheimer’s disease (AD). Herein, we report the brain gene expression profiles of severe COVID-19 patients showing increased expression of innate immune response genes and genes implicated in AD pathogenesis. The use of a mouse-adapted strain of SARS-CoV-2 (MA10) in an aged mouse model shows evidence of viral neurotropism, prolonged viral infection, increased expression of p-tau particularly in the brain parenchyma adjacent to CD31+ staining. Brain histopathology shows AD signatures including increased tau-phosphorylation, tau-oligomerization in aged MA10 infected mice. The results of gene expression profiling of SARS-CoV-2-infected and AD brains and studies in the MA10 aged mouse model taken together provide evidence suggesting that SARS-CoV-2 infection alters expression of genes in the brain associated with the development of AD.

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