Project Team

Steven Maier, PhD, Distinguished Professor Behavioral Neuroscience,  Director of the Center for Neuroscience, University of Colorado Boulder

Monika Fleshner, PhD, Professor in the Department of Integrative Physiology, Member of the Center for Neuroscience, Director of the Stress Physiology Laboratory, University of Colorado Boulder

Matthew Frank, PhD, Senior Research Associate. Psychology and Neuroscience, University of Colorado Boulder

Project lead Dr. Steven Maier

Project Summary:

A project to study whether “multiple hits” (e.g., different viral or bacterial infections) increase the risk of chronic symptom development and central nervous system microglia hyperactivation after SARS-CoV-2 infection. The project team will use viral protein mimics (poly I:C) and bacterial cell wall components (LPS) to model the microglia priming effects of previous virus activation and bacterial translocation respectively, in rodents. The hypothesis is that these will serve as first “hits” to sensitize neuroinflammatory processes, while the SARS-CoV-2 S1 protein will serve as a second “hit”, likely resulting in a heightened neuroinflammatory and behavioral response. To assess these changes, markers of proinflammatory cytokines, chemokines, microglia activation and other factors will be measured in brain tissue.

A second part of the project will determine if the SARS-CoV-2 S1 subunit in the periphery of the body can activate pro-inflammatory signaling in brain via the vagus nerve. The project team has previously demonstrated that the vagus nerve conveys inflammatory signals from the immune system in the body to the brain. A series of experiments will be performed to determine if the SARS-CoV-2 S1 protein in the colon can signal via receptors on vagus nerve fibers to produce a neuroinflammatory response in the brain.

Project Background:

The project team has 20+ years of experience studying processes and mechanisms of neuroinflammatory priming in rodent models of aging and stress. They recently used these models to show that the S1 subunit of the SARS-CoV-2 spike protein is sufficient to produce a neuroinflammatory and behavioral response that models several phenotypes of COVID-19. They have also demonstrated that the S1 subunit directly elicits a neuroinflammatory response in microglia, which is mediated by the pattern recognition receptor Toll-like receptor 4 (TLR4). The current project will expand on this work by using the rodent models to explore how multiple infectious “hits” might contribute to microgial priming and LongCOVID symptom mechanisms. Knowledge gained from the project could help guide the development of therapeutic interventions that target these mechanisms, thereby mitigating the debilitating effects of LongCOVID.