Tangled quest of post-COVID-19 infection-caused neuropathology and what 3P nano-bio-medicine can solve?

Abstract

COVID-19-caused neurological problems are the important post-CoV-2 infection complications, which are recorded in ~ 40% of critically ill COVID-19 patients. Neurodegeneration (ND) is one of the most serious complications. It is necessary to understand its molecular mechanism(s), define research gaps to direct research to, hopefully, design new treatment modalities, for predictive diagnosis, patient stratification, targeted prevention, prognostic assessment, and personalized medical services for this type of complication. Individualized nano-bio-medicine combines nano-medicine (NM) with clinical and molecular biomarkers based on omics data to improve during- and post-illness management or post-infection prognosis, in addition to personalized dosage profiling and drug selection for maximum treatment efficacy, safety with least side-effects. This review will enumerate proteins, receptors, and enzymes involved in CoV-2 entrance into the central nervous system (CNS) via the blood-brain barrier (BBB), and list the repercussions after that entry, ranging from neuroinflammation to neurological symptoms disruption mechanism. Moreover, molecular mechanisms that mediate the host effect or viral detrimental effect on the host are discussed here, including autophagy, non-coding RNAs, inflammasome, and other molecular mechanisms of CoV-2 infection neuro-affection that are defined here as hallmarks of neuropathology related to COVID-19 infection. Thus, a couple of questions are raised; for example, "What are the hallmarks of neurodegeneration during COVID-19 infection?" and "Are epigenetics promising solution against post-COVID-19 neurodegeneration?" In addition, nano-formulas might be a better novel treatment for COVID-19 neurological complications, which raises one more question, "What are the challenges of nano-bio-based nanocarriers pre- or post-COVID-19 infection?" especially in the light of omics-based changes/challenges, research, and clinical practice in the framework of predictive preventive personalized medicine (PPPM / 3P medicine).

Keywords: 3P nano-bio-medicine; Autophagy; Biomarker; Blood–brain barrier (BBB); Central nervous system (CNS); Hallmarks of neuropathology; Inflammasome; Multi-omics; Nano-medicine (NM); Nanotechnology; Neurodegeneration; Non-coding RNAs (ncRNA); Patient stratification; Personalized medical service; Post-COVID-19 complications; Post-CoV-2 infection; Predictive diagnosis; Predictive preventive personalized medicine (PPPM / 3P medicine); Prognostic assessment; SARS-CoV2; Targeted prevention.

Fig. 1

Mechanism(s) for SARS-CoV-2 entry to CNS (01) and neuronal target(s) for SARS-CoV-2 post entry (02). SARS-CoV-2 entry to the CNS occurs via BBB endothelial cells, viral spike proteins bind the host ACE2 receptors, with facilitated viral entry activating the viral envelope glycoproteins, and finally more interaction occurs via the host cofactor proteins neuropilins, MMPs, tyrosine kinase receptors, basigin, CD147, RAGE, and AGTR2. Post SARS-CoV-2 entry to the host cell, viral replication promotion occurs, induced host cell apoptosis plus cytokines and chemokines overproduction, with reduced host interferon formation, leads to host-cell necrosis, host mitochondrial and lysosomal dysfunction, and inflammasome and autophagy activation and caspase-independent host cell death, all are triggered via various viral-ORF-genes. v = virus

Fig. 2

Neurological post-COVID-19 manifestations, addressing mechanism(s) of long-COVID-19 complications within the nervous system tissues. Neuro-inflammation from CSS, ILs, TNF, and more infection-related neuro-invasion, cytokine storm syndrome increases IL-6 production and the BBB permeability leading to BBB endothelial cells disruption mechanisms

Fig. 3

Young vs aging BBB in response to SARS-CoV-2 infection

Fig. 4

List of hallmarks of SARS-CoV-2-infection-related neuropathology

Fig. 5

The hsa-miRs that target the virus particle/protein itself. v-miR-MR147-3p and v-miR-MR66-3p target host TMPRSS2, and the reverse human miRs target the viral envelope glycoprotein. Some host miRs affect the hACE2 receptor which binds viral-spike protein. Host miR-126 and -378 target the viral nucleocapsid protein

Fig. 6

Predictive, preventive, and personalized 3P nano-bio-medicine implementation during and post-pandemic era

Fig. 7

COVID-19-infection caused cytokine storm and current or future CoV-2 infection treatment attempts

Fig. 8

Post COVID-19-related neuro-affection manifestations summary