Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Howard E. Gendelman

Second Advisor

R. Lee Mosley

Abstract

Mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells) are the governors of innate immunity which is the body’s first line of defense against microbial pathogens. They act beneficial or detrimental. They are crucial for an effective non-specific immune response to invading pathogens by engulfing, destroying, then eliciting an adaptive specific immune response. Given their pivotal functions in the host immune defense, studying MP immune responses in disease is paramount important for understanding disease pathobiology and uncovering therapeutic strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the driver of acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) amongst other inflammatory end-organ morbidities. We investigated transcriptome and proteome of human macrophages following SARS-CoV-2 exposure. While expression of SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Lack of adequate antiviral innate immune responses in the front of cytokine storm heralds an absence of viral infection control that exacerbates clinical manifestations and contributes to end-organ damage for COVID-19-related morbidities and mortalities. Likewise, dysregulation of innate immunity defined by impairments in monocyte activation, function, and pro-inflammatory secretory factors heralds the development and progression of multiple neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Monocytes also affect neural function by imbalances between effector T (Teff) and regulatory T (Treg) cells. Changes in gene and protein expression were evaluated before and during treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine®). Transcriptome and proteome biomarkers were scored against clinical motor function. Single cell-RNA sequencing and proteomic results demonstrated a neuroprotective signature, including, but not limited to, antioxidant, anti-inflammatory, and autophagy genes and proteins (LRRK2, HMOX1, TLR2, TLR8, RELA, ATG7, and GABARAPL2).

Taken together, MP innate immune responses to SARS-CoV-2 reveals more effective therapeutic strategies for viral infections. Similarly, studying innate immune responses in PD uncovers more effective therapeutic strategies for neurodegenerative diseases and provides a novel strategy to track clinical immune modulatory therapies.

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