MiRNA-based Therapeutics for SARS-CoV-2 S1 mediated neuroinflammation and beta-amyloid production

Project summary/Abstract There is ample evidence that SARS-CoV-2, the causative agent of COVID-19, causes neurological symptoms but there is insufficient evidence that the virus can directly infect the brain. It has been suggested that neurological symptoms might be due to additional factors such as cytokine storm, neuroimmune stimulation, and systemic SARS-CoV-2 infection, rather than by direct CNS damage caused by the virus. The S protein is the main antigenic component of SARS- CoV-2 structural protein and its proteolytic processing allows the S1 subunit to dissociate, which then triggers the S2 subunit rearrangement that is required for fusion. Also, TLR4 is the most important member of the TLR family for pathogen recognition and helps to provide first line defense against infections through inflammatory factors induction. Herein, we propose to test the hypothesis that the cleaved S1 subunit itself enters the brain parenchyma causing neuroinflammation and b-amyloid accumulation and TLR4-targeted microRNA(s) can inhibit these processes. This hypothesis will be tested in two specific aims. First, we will test if S1 directly interacts with TLR4 in microglia and initiates immune responses that leads to excessive activation of the pathway, which disrupts immune homeostasis and results in chronic brain inflammation and b-amyloid accumulation. Second, we will test the role of specific miRNAs, selected using bioinformatics prediction tools, in regulating the S1-initiated neuroinflammation. After experimental validation of miRNA targets, specific miRNAs will be enriched in exosomes and tested for their ability to end the positive feedback loop between inflammation and b-amyloid production. The results are expected to provide mechanistic insights into the COVID-19 effects on neuroinflammation and dementia and lead to the development of miRNA therapeutics against covid-induced regulatory loop between inflammation and b-amyloid production.