Pathogen-associated molecular pattern (PAMP)
Several previous studies have suggested that the S protein of SARS-CoV-2 might function as a pathogen-associated molecular pattern (PAMP) to drive neuroinflammatory responses through activation of TLRs, which are widely expressed on macrophages and microglia and may function as pattern recognition receptors (PRRs) to recognize molecular sequences common to bacterial and viral pathogens. Microglia have been shown to express a wide range of PRRs, including TLRs, NOD-like receptors, RAGE and scavenger receptors. SARS-CoV-2 activates these receptors, possibly eliciting neuroinflammatory responses and contributing to disease progression and severity [19].
Astrocytes are also important components of the intrinsic immune response in the CNS following viral infection. An increased plasma concentration of glial fibrillary acidic protein (GFAP), a hallmark of astrocyte activation, is commonly detected in patients with moderate and severe COVID-19. As components of the BBB, astrocytes are highly sensitive to peripheral inflammation. In addition to responding to signals from microglia, astrocytes also rapidly respond to proinflammatory cytokines secreted by endothelial cells. Astrocytes express inflammatory molecules that contribute to neuroinflammation and neurodegeneration upon exposure to activated proinflammatory microglia, including proinflammatory cytokines such as IL-6, IL-1β and TNF-α; PAMPs; and danger-associated molecular patterns. These data clearly indicate that microglia and astrocytes participate in neuroinflammatory responses to viral infection of the CNS [20].