The Effect of COVID-19 on NF-κB and Neurological Manifestations of Disease

Abstract

The coronavirus disease that presumably began in 2019 (COVID-19) is a highly infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic. Initially, COVID-19 was thought to only affect respiration. However, accumulating evidence shows a wide range of neurological symptoms are also associated with COVID-19, such as anosmia/ageusia, headaches, seizures, demyelination, mental confusion, delirium, and coma. Neurological symptoms in COVID-19 patients may arise due to a cytokine storm and a heighten state of inflammation. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is a central pathway involved with inflammation and is shown to be elevated in a dose-dependent matter in response to coronaviruses. NF-κB has a role in cytokine storm syndrome, which is associated with greater severity in COVID-19-related symptoms. Therefore, therapeutics that reduce the NF-κB pathway should be considered in the treatment of COVID-19. Neuro-COVID-19 units have been established across the world to examine the neurological symptoms associated with COVID-19. Neuro-COVID-19 is increasingly becoming an accepted term among scientists and clinicians, and interdisciplinary teams should be created to implement strategies for treating the wide range of neurological symptoms observed in COVID-19 patients.

Keywords: COVID-19; Cognitive impairment; NF-κB; Neuro-COVID-19; Oxidative stress.

Fig. 1

COVID infection and NF-κB signaling. This putative pathway suggests that coronaviruses are able to cause inflammation in human brain through nuclear factor kappa B (NF-κB)-dependent signaling. Binding of viral SARS-CoV to its receptors, such as CD147, angiotensin-converting enzyme 2 (ACE2), and the help of the transmembrane serine protease 2 (TMPRSS2), allows SARS-CoV to enter into host cells through cleaving/activating of viral envelope glycoproteins. Within the endosomes, viral single-stranded RNA virus activates the Toll-like receptors (TLRs), such as TLR3, TLR4, and TLR7/8. These receptors activate IKK which results in phosphorylation of the cytoplasmic inhibitor factor IκBα, which in turn leads to phosphorylation of IκBα, and subsequent degradation. As a result, NF-κB p50 and p65 are released from IκBα and translocate from the cytoplasm into the nucleus to induce transcription of various genes coding for pro-inflammatory proteins such as cytokines and chemokines. Activated NF-κB is associated with a variety of cytokine receptor- and TLR-mediated signal cascades, including binding of TNFα or IL-1 to their receptors. Excessive NF-κB activation triggers production of pro-inflammatory cytokines and a chemokine storm. T cells such as CD4 and CD8 are then activated at the site of infection by cytokines and a chemokine storm and promote further inflammation. Additionally, dendritic cells trigger adaptive immunity. This figure was developed using the BioRender online software tool