Viral and Host Small RNA Response to SARS-CoV-2 Infection

Sun, Guihua; Cui, Qi; García, Gustavo; Lizhar, Elizabeth M.; Arumugaswami, Vaithilingaraja; Shi, Yanhong; Riggs, Arthur D.

doi:10.3390/microbiolres13040056

Cited by 4 publications

(4 citation statements)

References 51 publications

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“…Interestingly, it has been suggested that many RNA viruses contain "hotspots" that serve as sites for vsRNA production [62], whereby sequences surrounding hotspots might be expected to adopt stable hairpin-like structures predicted by RNAz within the conserved RNA structures [75,76]. This pattern was recently observed by comparing virally derived small RNAs in different SARS-CoV-2-infected samples that are prone to generate vsRNAs [77]. In our case, the vast majority of our Beta-CoV vsRNAs encoded in ORF1a at genome positions ranging from 4153 to 5544 seem to show possible "hotspots", indicating that the nsp3 of ORF1a is deeply involved in vsRNA production [78,79].…”

Section: Discussionmentioning

confidence: 91%

Computational Prediction of RNA–RNA Interactions between Small RNA Tracks from Betacoronavirus Nonstructural Protein 3 and Neurotrophin Genes during Infection of an Epithelial Lung Cancer Cell Line: Potential Role of Novel Small Regulatory RNA

Rojas-Cruz

Bermúdez-Santana

2023

Viruses

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Whether RNA–RNA interactions of cytoplasmic RNA viruses, such as Betacoronavirus, might end in the biogenesis of putative virus-derived small RNAs as miRNA-like molecules has been controversial. Even more, whether RNA–RNA interactions of wild animal viruses may act as virus-derived small RNAs is unknown. Here, we address these issues in four ways. First, we use conserved RNA structures undergoing negative selection in the genomes of SARS-CoV, MERS-CoV, and SARS-CoV-2 circulating in different bat species, intermediate animals, and human hosts. Second, a systematic literature review was conducted to identify Betacoronavirus-targeting hsa-miRNAs involved in lung cell infection. Third, we employed sophisticated long-range RNA–RNA interactions to refine the seed sequence homology of hsa-miRNAs with conserved RNA structures. Fourth, we used high-throughput RNA sequencing of a Betacoronavirus-infected epithelial lung cancer cell line (Calu-3) to validate the results. We proposed nine potential virus-derived small RNAs: two vsRNAs in SARS-CoV (Bats: SB-vsRNA-ORF1a-3p; SB-vsRNA-S-5p), one vsRNA in MERS-CoV (Bats: MB-vsRNA-ORF1b-3p), and six vsRNAs in SARS-CoV-2 (Bats: S2B-vsRNA-ORF1a-5p; intermediate animals: S2I-vsRNA-ORF1a-5p; and humans: S2H-vsRNA-ORF1a-5p, S2H-vsRNA-ORF1a-3p, S2H-vsRNA-ORF1b-3p, S2H-vsRNA-ORF3a-3p), mainly encoded by nonstructural protein 3. Notably, Betacoronavirus-derived small RNAs targeted 74 differentially expressed genes in infected human cells, of which 55 upregulate the molecular mechanisms underlying acute respiratory distress syndrome (ARDS), and the 19 downregulated genes might be implicated in neurotrophin signaling impairment. These results reveal a novel small RNA-based regulatory mechanism involved in neuropathogenesis that must be further studied to validate its therapeutic use.

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Section: Discussionmentioning

confidence: 91%

Computational Prediction of RNA–RNA Interactions between Small RNA Tracks from Betacoronavirus Nonstructural Protein 3 and Neurotrophin Genes during Infection of an Epithelial Lung Cancer Cell Line: Potential Role of Novel Small Regulatory RNA

Rojas-Cruz

Bermúdez-Santana

2023

Viruses

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“…There are now numerous studies regarding the effects of COVID-19 infection upon miRNA production, both by cells in response to the infection, and by SARS-CoV-2 to promote its own successful infection [99][100][101][102][103][104][105][106][107][108][109][110]. These studies include the effects on gene expression, altered biochemical pathways, interferon signaling, interaction with host mRNAs, and have demonstrated that various miRNAs appear associated with clinical severity including inflammatory and cytokine storm mechanisms [93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110]. One study has identified both chemokine (CC) CCL20, inflammatory cytokines IL6 and IL10, and miR-451a as key correlates of fatal COVID-19 [110], i.e., miRNAs are part of a wider whole system response.…”

Section: Covid-19 Infection Alters the Mirna Landscape And Ensuing Ge...mentioning

confidence: 99%

The nonspecific effects of COVID-19 vaccination upon non-COVID-19 all-cause mortality (NCACM) in the population of England: Effects of age, sex, COVID-19 variant, vaccination history, and time in a real-world study from Jan-21 to May-23

Jones,

Ponomarenko

2024

Preprint

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All vaccines exhibit specific and nonspecific effects. Specific effects are shown by the efficacy against the target pathogen, while nonspecific effects can be detected by the change in all-cause mortality. The real-world non-COVID-19 all-cause mortality (NCACM) data for the population of England between January 2021 and May 2023 was assessed. All vaccines administered were based on the original Wuhan antigen. Each gender and age group, along with COVID-19 variant shows its own unique NCACM vaccination benefit/disbenefit time profile. The efficacy of COVID-19 vaccination against COVID-19 disease/death per se is undisputed, however, the nonspecific outcomes of COVID–19 vaccination is far more nuanced than have been widely appreciated. This confirms an earlier study on the unanticipated nonspecific effects of influenza vaccination against all-cause winter mortality. Interestingly, a high proportion of NCACM beneficial effects occurred during the first 21 days following COVID-19 vaccination, while the worst example of increased NCACM occurred during the fourth dose of COVID-19 vaccination in 19–40-year-olds for the interval &gt;21 days post vaccination which led to NCACM 3- to 10-times higher than in the unvaccinated. By the time of the Omicron variant, NCACM outcomes in those aged 90+ are mostly adverse. The beneficial nonspecific effects of COVID-19 vaccination increase with age and reach their maximum effect during the second week post vaccination for age groups below 50 years, rising to during the third week for those aged 70+. Finally, we discuss the mechanisms by which COVID-19 vaccination could induce wider nonspecific effects. Most of these mechanisms seem to depend on gene regulation by noncoding RNAs which also interact with mRNAs. We suggest that further international studies are required to discern the nonspecific NCACM effects of the different COVID-19 variants other than the three variants prevalent in the UK, and different types/manufacturer of COVID-19 vaccines which have been employed around the world. We can only speculate regarding the nonspecific effects of the COVID-19 vaccines administered to persons with an asymptomatic infection, and during vaccine waning. Vaccines not only need to be effective against the target pathogen, as primarily determined by antibody production, but need to minimize any unanticipated adverse nonspecific effects against all-cause mortality.

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“…Increasing evidence suggests the existence of a close relationship between the SARS-CoV-2 infection and the altered accumulation of endogenous small non-coding RNAs (sncRNAs, or simply sRNAs) 6 , 8 – 11 . Of note, sncRNAs are pervasive in all kingdoms of life (from prokaryotes to eukaryotes) and they are involved in the regulation of gene expression 12 .…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity

Corell-Sierra,

Marquez-Molins,

Marqués

et al. 2024

npj Syst Biol Appl

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The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has significantly impacted global health, stressing the necessity of basic understanding of the host response to this viral infection. In this study, we investigated how SARS-CoV-2 remodels the landscape of small non-coding RNAs (sncRNA) from a large collection of nasopharyngeal swab samples taken at various time points from patients with distinct symptom severity. High-throughput RNA sequencing analysis revealed a global alteration of the sncRNA landscape, with abundance peaks related to species of 21-23 and 32-33 nucleotides. Host-derived sncRNAs, including microRNAs (miRNAs), transfer RNA-derived small RNAs (tsRNAs), and small nucleolar RNA-derived small RNAs (sdRNAs) exhibited significant differential expression in infected patients compared to controls. Importantly, miRNA expression was predominantly down-regulated in response to SARS-CoV-2 infection, especially in patients with severe symptoms. Furthermore, we identified specific tsRNAs derived from Glu- and Gly-tRNAs as major altered elements upon infection, with 5’ tRNA halves being the most abundant species and suggesting their potential as biomarkers for viral presence and disease severity prediction. Additionally, down-regulation of C/D-box sdRNAs and altered expression of tinyRNAs (tyRNAs) were observed in infected patients. These findings provide valuable insights into the host sncRNA response to SARS-CoV-2 infection and may contribute to the development of further diagnostic and therapeutic strategies in the clinic.

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Viral and Host Small RNA Response to SARS-CoV-2 Infection

Cited by 4 publications

References 51 publications

Computational Prediction of RNA–RNA Interactions between Small RNA Tracks from Betacoronavirus Nonstructural Protein 3 and Neurotrophin Genes during Infection of an Epithelial Lung Cancer Cell Line: Potential Role of Novel Small Regulatory RNA

Computational Prediction of RNA–RNA Interactions between Small RNA Tracks from Betacoronavirus Nonstructural Protein 3 and Neurotrophin Genes during Infection of an Epithelial Lung Cancer Cell Line: Potential Role of Novel Small Regulatory RNA

The nonspecific effects of COVID-19 vaccination upon non-COVID-19 all-cause mortality (NCACM) in the population of England: Effects of age, sex, COVID-19 variant, vaccination history, and time in a real-world study from Jan-21 to May-23

SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity

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