Abstract

The complement system is an ancient pathway that serves dual roles as a key regulator of neuroinflammation and a critical regulator of neural networks. Few studies have addressed how these two pathways may interact during infection of the central nervous system. While some components of complement are expressed in the healthy developing brain, complement component 3a receptor (C3aR) is a G protein coupled receptor that is expressed by astrocytes, microglia and infiltrating immune cells during inflammatory states. We previously found that C3aR is required for engulfment of synaptic material by activated microglia during neuroinvasive viral infection. Here, we used a mouse model of West Nile neuroinvasive disease (WNND) to further address the role of C3aR during WNND. We examined its expression and function in the setting of acute infection in both wild-type versus C3aR-deficient mice, and C3aR-microglia specific conditional KO mice. First, we demonstrate that C3aR levels peak during acute infection, and the receptor is expressed primarily on myeloid cells. C3aRKO infected mice exhibit decreased resident and infiltrating myeloid cell numbers during acute infection, and a corresponding decrease in synapse elimination in the retrosplenial cortex, a region implicated in spatial learning and memory. Conditional deletion of C3ar from microglia leads to specific decreases in the resident myeloid cell population during acute infection, and decreased synapse elimination in the retrosplenial cortex. We also show that the changes in myeloid cell populations are linked to increased caspase-3 activity in these cells. Additionally, we explore the role of complement component C1q. Upon direct binding to pathogen surfaces or antibody-antigen complexes, C1q initiates enzymatic activity that results in downstream cleavage of classical cascade components. We have previously identified virally infected neurons and activated microglia as sources of CNS C1q during WNND. Here, we provide preliminary evidence for a dual role for C1q in synapse elimination and virologic control. We also demonstrate that this ligand may be a useful biomarker for cognitive dysfunction post recovery from WNND. All together, these results provide further insight into the role(s) of complement signaling in mediating viral neuroinflammatory responses.

Committee Chair

Robyn Klein

Committee Members

Miguel Faria-e-Castro; Michele Boldrin; Ping Wang; Rodolfo Manuelli

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-5-2025

Language

English (en)

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