SARS-CoV-2 interacts with renin-angiotensin system: impact on the central nervous system in elderly patients

Abstract

SARS-CoV-2 is a recently identified coronavirus that causes the current pandemic disease known as COVID-19. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, suggesting that the initial steps of SARS-CoV-2 infection may have an impact on the renin-angiotensin system (RAS). Several processes are influenced by RAS in the brain. The neurological symptoms observed in COVID-19 patients, including reduced olfaction, meningitis, ischemic stroke, cerebral thrombosis, and delirium, could be associated with RAS imbalance. In this review, we focus on the potential role of disturbances in the RAS as a cause for central nervous system sequelae of SARS-CoV-2 infection in elderly patients.

Keywords: COVID-19; Central nervous system; Elderly; Renin-angiotensin system; SARS-CoV-2.

Fig. 1

Proposed routes of SARS-CoV2 neuroinvasion. Viruses enter the vascular pathways and spread toward the CNS through the vagus nerve branch that innervates the respiratory and gastrointestinal tract. SARS-CoV-2 could also enter the respiratory tract into the bloodstream through ACE2 receptors expressed in type II alveolar epithelial cells of the respiratory tract and also after infection of enterocytes at the gastrointestinal tract. Bloodstream invasion by the virus may increase when endothelial cells of the BBB are infected and cell-to-cell adhesion disrupted, allowing for paracellular transmigration of virions involving ICAM-1-mediated transport that is upregulated by TNF-α and MMPs activation, which promote destabilization or disruption of tight junctions of the BBB leading to BBB leakage that is exacerbated by the cytokine storm. Additionally, the presence of viral nucleotide sequences in macrophages and T lymphocytes distributed at the periphery of germinal centers, lymph nodes, and in peripheral blood suggests that SARS-CoV-2 could use a “Trojan horse”-type mechanism by infecting T cells, macrophages, and monocytes in the blood

Fig. 2

SARS-CoV-2 entry into the brain activates microglia and induces astrogliosis, increasing the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) and prostaglandin E2 (PGE2), leading to chronic inflammation, neural hyperexcitability, and exacerbated neuron programmed cell death. Levels of Ang-II are increased lead to exacerbated inflammatory responses observed in COVID-19 since Ang-II potently activates NF-kB in different cell types. An increase in activity of the Ang-II pathway would be more harmful in older patients because of its exacerbated inflammatory component which leads to hyper-inflammation. ACE2 expression is also high in brain pericytes that could be permissive of infection with SARS-CoV-2 and able to spread the virus to astrocytes mediating inflammatory interferon-type I (IFN-I) transcription

Fig. 3

RAS starts with the synthesis of protease renin in the kidney, which produces Ang-I from angiotensinogen in the liver. Ang-I is transformed in Ang-II by the action of ACE. Secondly, Ang (1–7) is produced by the action of ACE2 on Ang-II. RAS function is dependent on the balance of two opposing pathways. One formed by Ang-II, and the AT1R (inflammatory way), and the other comprises Ang (1–7) that intervenes in its actions by binding to Mas receptor and Ang-II /AT2R (anti-inflammatory way). The aging process unbalances the RAS activation promoting abnormal levels of inflammation, oxidative stress with concomitant cell death. AT1R and Ang-II levels are upregulated during aging. In contrast to the counterbalanced components, AT2R and Ang (1–7)/Mas axis expression appeared to be decreed. This process could be exacerbated during SARS-CoV-2 infection and explain the accelerated neurodegenerative manifestation observed in aging phenotypes of COVID-19 patients