The Infected Lungs and Brain Interface in COVID-19: The Impact on Cognitive Function

Abstract

Many coronavirus disease 2019 (COVID-19)-recovered patients report signs and symptoms and are experiencing neurological, psychiatric, and cognitive problems. However, the exact prevalence and outcome of cognitive sequelae is unclear. Even though the severe acute respiratory syndrome coronavirus 2 has target brain cells through binding to angiotensin-converting enzyme 2 (ACE2) receptor in acute infection, several studies indicate the absence of the virus in the brain of many COVID-19 patients who developed neurological disorders. Thus, the COVID-19 mechanisms for stimulating cognitive dysfunction may include neuroinflammation, which is mediated by a sustained systemic inflammation, a disrupted brain barrier, and severe glial reactiveness, especially within the limbic system. This review explores the interplay of infected lungs and brain in COVID-19 and its impact on the cognitive function.

Keywords: COVID-19; Cognitive dysfunction; Neuroinflammation; SARS-CoV-2.

Fig. 1

Schematic of the SARS-CoV-2 infection. (1) The S protein binds to the receptor ACE2. (2) Cleavage of SARS-COV-2 S protein. (3) Activation of S2 domain. (4) The virus-cell fusion process.

Fig. 2

Routes of entry for the COVID-19 virus in the CNS. (1) The first route of entry would be through the olfactory epithelium, crossing the cribriform plate of the ethmoid bone and reaching the olfactory bulb from which it could spread to different areas of the brain. (2) The second route would be through the activation and permeability of BBB. The virus in the bloodstream may infect the peripheral immune cells and cause the cytokine storm. Cytokines can signal and alter the structure of BBB, and infected leukocytes could enter the CNS through dysfunctional brain barriers, acting as a vehicle for dissemination within the CNS or aggravate cytokine production within the CNS. (3) Another mechanism would be through the neuronal pathway in the lower respiratory tract through thevagus nerve, where viruses are transported by endocytosis and exocytosis through neuronal cell bodies.

Fig. 3

SARS-CoV-2-mediated cognitive impairment. After entry into the epithelial cells, the virus activates NF-κB and JAK/STAT pathway by TLR binding and leads to the production of TNF-α, IL-1β, IL-6, IFN-γ, CXCL10, MIP-1α and -1β, and VEGF. The cytokines stimulate the production of C-reactive protein and promote T-cell apoptosis, suppress T-cell activation, and IFN-γ production. The cytokines and chemokines attract immune cells from the circulation, like the monocytes, macrophages, T cells, and neutrophils, to the site of infection. Additionally, TNF-α, IL-4, IL-6, IL-12, and IL-23 further recruit the immune cells, establishing a pro-inflammatory feedback loop that leads to BBB permeability and stimulates microglia and astrocyte responsiveness. Consequently, these cells produce more inflammatory mediators that exert neurotoxic effects, promoting neuronal dysfunction and cognitive impairment.