Genetic Exchange of Lung-Derived Exosome to Brain Causing Neuronal Changes on COVID-19 Infection

Abstract

The pandemic of novel coronavirus 2 (SARS-CoV-2) has made global chaos for normal human living. Despite common COVID-19 symptoms, variability in clinical phenotypes was reported worldwide. Reports on SARS-CoV-2 suggest causing neurological manifestation. In addition, the susceptibility of SARS-CoV-2 in patients with neurodegenerative diseases and its complexity are largely unclear. Here, we aimed to demonstrate the possible transport of exosome from SARS-CoV-2–infected lungs to the brain regions associated with neurodegenerative diseases using multiple transcriptome datasets of SARS-CoV-2–infected lungs, RNA profiles from lung exosome, and gene expression profiles of the human brain. Upon transport, the transcription factors localized in the exosome regulate genes at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions of Parkinson’s disease (PD) and frontal cortex, hippocampus, and temporal cortex of Alzheimer’s disease (AD). On SARS-CoV-2 infection, BCL3, JUND, MXD1, IRF2, IRF9, and STAT1 transcription factors in the exosomes influence the neuronal gene regulatory network and accelerate neurodegeneration. STAT1 transcription factor regulates 64 PD genes at lateral substantia nigra, 65 at superior frontal gyrus, and 19 at medial substantia nigra. Similarly, in AD, STAT1 regulates 74 AD genes at the temporal cortex, 40 genes at the hippocampus, and 16 genes at the frontal cortex. We further demonstrate that dysregulated neuronal genes showed involvement in immune response, signal transduction, apoptosis, and stress response process. In conclusion, SARS-CoV-2 may dysregulate neuronal gene regulatory network through exosomes that attenuate disease severity of neurodegeneration. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02485-9.

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Additionally, in terms of individual genes in the turquoise module, we identified hub-high traffic genes such as UTP14A ( 398 ), RUVBL2 ( 139 ), PRKCD ( 280 , 399 ), KEAP1 ( 400 – 402 ), CEBPA (TF) ( 403 ), RPL26L1 ( 404 ), PTPN6 ( 255 ), PPARA (TF) ( 405 ), TNFRSF1A ( 406 – 408 ), IKBKB ( 275 , 409 ), TFEB (TF) ( 410 , 411 ), PSMD4 ( 412 ), and ARHGAP1 ( 413 ), important components in immunopathogenesis of SARS-CoV-2. For example, the TNF receptor superfamily member 1A ( TNFRSF1A ) hub-high traffic gene may be a biomarker of mortality in severe COVID-19 patients, as increased expression of this gene was significantly correlated with mortalities ( 414 ).…”

Post-COVID-19 Parkinsonism and Parkinson’s Disease Pathogenesis: The Exosomal Cargo Hypothesis

“…The neurological consequences of SARS-CoV-2 infection, according to Ahmed and colleagues, could be attributed, at least in part, to exosomal mRNA and transcriptional factors (Tfs) carried from the lungs to the brain areas [ 327 ]. These exosomal Tfs have the ability to regulate cellular gene expression transcriptionally and induce neuronal alterations consistent with imminent neurodegeneration.…”

Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population

“…Moreover, it was shown that an increased mutation rate in the KLHL1 gene was associated with lifetime benzo(a) pyrene exposure in patients with air-pollution-related lung cancers (Yu et al, 2015). Transcriptional factors JUND and FOXA1 binding sites are found in the proximity of the lead variant rs61964606 and both have been related to gene expression regulation in previous studies of SARS-CoV-2 infection (Qiao et al, 2020;Ahmed et al, 2021).…”