The SARS-CoV-2 S1 spike protein subunit potentiates the neuroinflammatory response to a subsequent immune challenge.

Nguyen, Tina H

Undergraduate Honors Thesis

The SARS-CoV-2 S1 spike protein subunit potentiates the neuroinflammatory response to a subsequent immune challenge. Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/xs55md79g

Abstract

By February 2021, the global death toll from SARS-CoV-2 reached approximately 2.5 million individuals. Evidence suggests that the S1 spike protein subunit of SARS-CoV-2 may initiate neuroinflammation through pattern recognition receptors (PRRs), contributing to post-acute sequelae of COVID-19 (PASC) manifestations, including cognitive and neuropsychiatric problems. However, it remains unclear whether persistent microglial activation beyond the acute phase modulates behavioral and neuroinflammatory responses, potentially priming microglia in a sustained proinflammatory state, introduced by the “two-hit” model. Therefore, we investigated whether the S1 spike protein would potentiate the neuroinflammatory response in the hypothalamus to a subsequent immune challenge of a bacterial mimetic. Adult male Sprague-Dawley rats received intra-cisterna magna (ICM) injections of vehicle or S1, followed by intraperitoneal (IP) injections of the bacterial mimetic, lipopolysaccharide (LPS), or vehicle 7 days later. Two days after LPS, neuroimmune gene expression was measured in the hypothalamus. Independent of LPS, S1 increased neuroimmune gene expression of MHCII, IL-6, and NLRP3 in the hypothalamus, indicative of heightened neuroinflammation from S1. S1 potentiated the effect of LPS on IL-1b and CD200R1. These findings underscore the potential of SARS-CoV-2 S1 spike protein subunits to exacerbate the neuroinflammatory process to subsequent immune challenges, potentially contributing to neurological manifestations of PASC.

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