Date of Award
December 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Sciences
First Advisor
Xuesong Chen
Abstract
The COVID-19 pandemic has led to widespread reports of prolonged neurological symptoms in individuals who have recovered from the acute phase of the infection. These persistent symptoms, collectively termed Neuro-PASC (Neurological Post-Acute Sequelae of SARS-CoV-2 infection), range from cognitive impairments to mood disturbances and other neuroinflammatory issues. Pathological features of Neuro-PASC include vascular impairment, neuroinflammation, and neurodegeneration. One leading hypothesis for the development of Neuro-PASC is the persistent of SARS-CoV-2 viral factors. Post-mortem evidence indicates that the spike protein of SARS-CoV-2 is consistently found in the brains of individuals who died with COVID-19, indicating that viral components can interact with central nervous system cells. Research has shown that the S1 subunit of the spike protein, a fragment released from the viral particle, can cross the blood-brain barrier, and persist in various cells and tissues throughout the body post-acutely. This study investigates the molecular and cellular mechanisms by which the S1 subunit may drive neuroinflammation, specifically focusing on its interactions with astrocytes, the brain’s primary glial cells responsible for maintaining central nervous system (CNS), homeostasis.
Findings from this research reveal that the S1 subunit independently induces a potent inflammatory response in astrocytes, implicating it as a direct contributor to the chronic immune activation observed in Neuro-PASC. S1 exposure prompts the release of key pro-inflammatory cytokines, including IL-6 and CCL2, which can compromise the blood-brain barrier and attract immune cells into the CNS, perpetuating neuroinflammation. Notably, the multibasic cleavage site within S1 amplifies these inflammatory effects, marking it as a significant modulator of astrocytic cytokine release.
Beyond inflammation, S1 was also found to disrupt astrocytic lysosomal function, leading to increased lysosomal permeability and the release of enzymes like cathepsins B and D. This lysosomal dysfunction, evidenced by Galectin-3 puncta formation and altered morphology, suggests a mechanism by which S1-induced cellular stress in astrocytes contributes to persistent neuroinflammation and cellular damage. Mechanistically, toll-like receptor 7 emerges as a critical mediator in this response, with S1’s interaction with TLR7 selectively activating inflammatory pathways. TLR7 knockdown effectively mitigates the inflammatory response and lysosomal damage caused by S1, highlighting its central role in astrocyte dysfunction.
Furthermore, exposure to S1 induces a senescence-like state in astrocytes, characterized by increased expression of p16 and SA-β-galactosidase. The research further examined the pathways involved in the TLR7 and S1-mediated responses, identifying the p38 MAPK signaling pathway as a crucial driver of the observed pro-senescent and inflammatory effects. Inhibition of p38 MAPK reduces S1-induced IL-6 release and senescence markers, underscoring p38’s role in S1-driven astrocytic inflammation and aging. By promoting astrocyte senescence and chronic inflammation, S1 may contribute to neurodegenerative processes, potentially explaining the cognitive and mood disturbances seen in Neuro-PASC patients.
These findings offer crucial insights into how the SARS-CoV-2 S1 subunit promotes inflammation, lysosomal dysfunction, and cellular senescence in astrocytes. Therapeutic strategies that target TLR7 and p38 MAPK signaling could provide promising avenues to alleviate the neurological impacts of Long COVID. This research advances our understanding of viral protein persistence in the CNS and highlights potential intervention points to mitigate SARS-CoV-2-induced astrocyte dysfunction and neurodegeneration in Neuro-PASC patients.
Recommended Citation
Hasler, Wendie Ann, "Endolysosomal Mechanisms of SARS-CoV-2 Spike-Induced Inflammatory Response And Senescence In Human Astrocytes" (2024). Theses and Dissertations. 6532.
https://commons.und.edu/theses/6532