There are mechanisms in the brain that regulate interactions between neurons and microglial cells and promote homeostasis. These are perturbed in several diseases including neuropsychiatric lupus, NPSLE, studied in this PPG, and following sepsis. Many conditions of neuroinflammation are characterized by microglial activation, and, as a consequence of this activation, by neuronal dendritic pruning and an impaired blood brain barrier. Interestingly, a pathway regulating homeostasis in the brain and dysregulated by neuroinflammation is the renin-angiotensin system. Angiotensin II is generated by angiotensin converting enzyme, ACE, and binds to a receptor AT-1 to enhance inflammation. ACE inhibitors or angiotensin receptor blockers, ARBs, can improve neuroinflammation by either decreasing production or neutralizing angiotensin II. In this pathway, ACE2, a membrane-bound protease, also functions to destroy angiotensin and to generate a small angiotensin peptide, ang1-7, that is anti-inflammatory. ACE2 is the cellular receptor for Covid-19, and binds the viral spike protein, S, more specifically, the receptor binding domain, RBD. This study will examine the binding of S and RBD to normal mouse brain and to mouse brain mimicking NPSLE or sepsis survival. We will further study whether engagement by S or RBD alters the functional state of neurons, microglia and brain endothelial cells. Finally, we ask whether the use of ACE inhibitors or ARBs alters S or RBD binding, and whether S or RBD impair the efficacy of these medications in halting or reversing the neurodegenerative process in NPSLE and in sepsis survivors. This study cannot be performed in humans, but it has important translational implications.
The goal of this study is to understand how the spike protein and its receptor binding domain affect the function of neurons, microglia and brain microvascular epithelial cells, all of which express ACE2, the receptor for Covid-19. We will study their binding and functional consequences in normal brain and in brain characterized by microglial inflammation. We will also ask how medications which regulate the ACE2 pathway affect the binding and function of S and RBD.
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