Distinct Mucoinflammatory Phenotype and the Immunomodulatory Long Noncoding Transcripts Associated with SARS-CoV-2 Airway Infection

Abstract

Respiratory epithelial cells are the primary target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated the 3D human airway tissue model to evaluate innate epithelial cell responses to SARS-CoV-2 infection. A SARS-CoV-2 clinical isolate productively infected the 3D-airway model with a time-dependent increase in viral load (VL) and concurrent upregulation of airway immunomodulatory factors (IL-6, ICAM-1, and SCGB1A1) and respiratory mucins (MUC5AC, MUC5B, MUC2, and MUC4), and differential modulation of select long noncoding RNAs (lncRNAs i.e., LASI, TOSL, NEAT1, and MALAT1). Next, we examined these immunomodulators in the COVID-19 patient nasopharyngeal swab samples collected from subjects with high- or low-VLs (~100-fold difference). As compared to low-VL, high-VL patients had prominent mucoinflammatory signature with elevated expression of IL-6, ICAM-1, SCGB1A1, SPDEF, MUC5AC, MUC5B, and MUC4. Interestingly, LASI, TOSL, and NEAT1 lncRNA expressions were also markedly elevated in high-VL patients with no change in MALAT1 expression. In addition, dual-staining of LASI and SARS-CoV-2 nucleocapsid N1 RNA showed predominantly nuclear/perinuclear localization at 24 hpi in 3D-airway model as well as in high-VL COVID-19 patient nasopharyngeal cells, which exhibited high MUC5AC immunopositivity. Collectively, these findings suggest SARS-CoV-2 induced lncRNAs may play a role in acute mucoinflammatory response observed in symptomatic COVID-19 patients.

Co-Regulation of Protein Coding Genes by Transcription Factor and Long Non-Coding RNA in SARS-CoV-2 Infected Cells: An In Silico Analysis

“…Expressions of hundreds of lncRNAs including uncharacterized novel transcripts have been identified in SARS-CoV-2 infected cells [32][33][34][35], BALF from the COVID-19 patients [35,36], and PBMC from COVID-19 patients [36][37][38][39]). In most of the studies, reanalyses of expression data for lncRNA from published transcriptomic data, except in two studies [33,37] were carried out. Combining the all-published results, expression of 87 lncRNA was increased and 283 lncRNA was decreased only in one study.…”

“…Analyzing PCG co-expressed with the lncRNA or identifying interacting partners of the lncRNA from various databases and enrichment analyses inferred the possible role of the deregulated lncRNA in the pathogenesis of COVID-19. Such studies revealed that increased expression of LASI (antisense strand to ICAM-1, not annotated in NCBI and Ensembl database), TOSL (TNFAIP3-opposite strand lncRNA, not annotated in NCBI and Ensembl database) and NEAT1 might be involved in immunomodulation [33]. Analyzing the PCGs that modulate the expression of genes by acting in cis or trans as evident from the correlation of lncRNA-PCG, it has been inferred that MALAT1 and NEAT1 possibly contributed to the inflammation developed in the SARS-CoV-2 infected cells [36].…”

“…Very recently it has been shown that that NEAT1 and MALAT1 are highly expressed in saliva and nasopharyngeal swab samples of COVID-19 patients [118] confirming the result in the present study. Increased in our earlier study [34] HCG11, HIF1A-AS2, LINC00115, LINC00174, LINC00265, LINC00312, LINC00473, LINC00605, LINC00662, LINC00842, MALAT1, MEG3, MEG9, MIAT, NEAT1, RMRP, hTR/TERC, ZNF674-AS1 (20) Decreased in the present study ARIH2OS, C1orf220, DANCR, DGCR5, DHRS4-AS1, DLEU1, DLGAP1-AS1, FAM201A, FLJ20021, FOXN3-AS1, GAS6-AS1, H19, KANSL1-AS1, LINC00526, LINC00707, LINC00880, LINC00893, MIR1915HG, NBR2, NCBP2AS2, PXN-AS1, RASSF8-AS1, SLC22A18AS, SLC25A21-AS1, SNHG32, SNHG5, SNHG9, ST7-AS1, TMEM161B-AS1, TMEM99, TMPO-AS1, TP53TG1, and WAC-AS1 (33) Decreased in our earlier study [34] LINC00488, LINC00857, PART1, and TP53TG1 (4)…”

“…Direct evidence that lncRNA is involved in the pathogenesis of COVID-19 is not available. Bioinformatics analysis with interacting partners of deregulated lncRNA in SARS-CoV-2 infected cells and comparison with experimental evidence for other viral infections inferred possible relevance of deregulated lncRNA in COVID-19 [32][33][34][35][36][37][38][39]. In the present study, in silico analysis revealed further that lncRNA interacting PCGs (i) interacted with SARS-CoV-2 coded proteins, (ii) deregulated SARS-CoV-2 infected cells, (iii) were modulated by interferon treatment, and (iv) modulated SARS-CoV-2 infection identified in a CRISPR screen.…”

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

“…SARS-CoV-2, as an RNA virus, shifts cell metabolism from oxidative phosphorylation to glycolysis, which triggers excessive inflammatory responses and cytokine storms ( Mahrooz et al, 2021 ), indicating that cellular metabolism is closely linked to SARS-CoV-2 infection. LncRNA is differentially expressed in COVID-19-infected patients ( Devadoss et al, 2021 ; Taheri et al, 2021 ). Therefore, the speculation above may also occur in SARS-CoV-2 infection, giving us a great impetus to explore the relationship between LncRNA, glycolysis, and antiviral innate immunity.…”