Abstract
The COVID-19 pandemic exerts inflammation-related parasympathetic complications and post-infection manifestations with major inter-individual variability. To seek the corresponding transcriptomic origins for the impact of COVID-19 infection and its aftermath consequences, we sought the relevance of long and short non-coding RNAs (ncRNAs) for susceptibility to COVID-19 infection. We selected inflammation-prone men and women of diverse ages among the cohort of Genome Tissue expression (GTEx) by mining RNA-seq datasets from their lung, and blood tissues, followed by quantitative qRT-PCR, bioinformatics-based network analyses and thorough statistics compared to brain cell culture and infection tests with COVID-19 and H1N1 viruses. In lung tissues from 57 inflammation-prone, but not other GTEx donors, we discovered sharp declines of the lung pathology-associated ncRNA DANCR and the nuclear paraspeckles forming neuroprotective ncRNA NEAT1. Accompanying increases in the acetylcholine-regulating transcripts capable of controlling inflammation co-appeared in SARS-CoV-2 infected but not H1N1 influenza infected lung cells. The lung cells-characteristic DANCR and NEAT1 association with inflammation-controlling transcripts could not be observed in blood cells, weakened with age and presented sex-dependent links in GTEx lung RNA-seq dataset. Supporting active involvement in the inflammatory risks accompanying COVID-19, DANCR’s decline associated with decrease of the COVID-19-related cellular transcript ACE2 and with sex-related increases in coding transcripts potentiating acetylcholine signaling. Furthermore, transcription factors (TFs) in lung, brain and cultured infected cells created networks with the candidate transcripts, indicating tissue-specific expression patterns. Supporting links of post-infection inflammatory and cognitive damages with cholinergic mal-functioning, man and woman-originated cultured cholinergic neurons presented differentiation-related increases of DANCR and NEAT1 targeting microRNAs. Briefly, changes in ncRNAs and TFs from inflammation-prone human lung tissues, SARS-CoV-2-infected lung cells and man and woman-derived differentiated cholinergic neurons reflected the inflammatory pathobiology related to COVID-19. By shifting ncRNA differences into comparative diagnostic and therapeutic profiles, our RNA-sequencing based Resource can identify ncRNA regulating candidates for COVID-19 and its associated immediate and predicted long-term inflammation and neurological complications, and sex-related therapeutics thereof. Our findings encourage diagnostics of involved tissue, and further investigation of NEAT1-inducing statins and anti-cholinergic medications in the COVID-19 context.
Highlights
The COVID-19 pandemic presents an ongoing challenge to the medical and research community
We mined RNA sequencing (RNA-seq) datasets from 57 inflammation-prone Genotype-Tissue Expression (GTEx) individuals whose lung tissues expressed at least seven of the eight representative inflammation-related transcripts including IL-1b, IL-6, TNFa, NFkB1\2, REL, and RELA\B [52]. These findings were compared to those of the 506 non-inflammationprone healthy men and women at different age groups, including lung and blood datasets. Both lung and blood samples from the inflammation-prone individuals expressed large numbers of massively downregulated differentially expressed (DE) messenger RNA (mRNA) and long non-coding RNA (lncRNA) compared to the non-inflammation-prone samples (Figures 1A, B), potentially pointing at the transcriptomic interlinks connecting between the studied transcripts as relevant for the risk of infection
We discovered the lung pathologyassociated lncRNA DANCR and the nuclear paraspeckles forming neuroprotective lncRNA NEAT1 as potentially involved in the susceptibility to and consequences of COVID19, in conjunction with acetylcholine and inflammationregulating transcripts
Summary
The COVID-19 pandemic presents an ongoing challenge to the medical and research community. SARS-CoV-2 is estimated to have infected globally more than 25 million people and claimed the lives of at least 800,000 by August 30th, 2020 (World Health Organization COVID-19 Weekly Epidemiological Update, retrieved September 5th, 2020). The clinical natural history of COVID-19, generated by SARS-COV-2, includes 4–6 days of incubation time, followed by a febrile and respiratory-focused clinical picture, and occasionally complicated by superinfection and multiple organ failure. Predicting who is at risk for severe complications is challenging, as accumulating follow-up data is still insufficient [9,10,11], and the realm of delayed cognitive risks has not yet been addressed
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