key: cord-0771734-einxzk0g authors: Mangukia, Naman; Rao, Priyashi; Patel, Kamlesh; Pandya, Himanshu; Rawal, Rakesh M. title: Unveiling the nature's fruit basket to computationally identify Citrus sinensis csi-mir169–3p as a probable plant miRNA against Reference and Omicron SARS-CoV-2 genome date: 2022-04-08 journal: Comput Biol Med DOI: 10.1016/j.compbiomed.2022.105502 sha: 26d7d4277f43588a6c5f6707341472dcd0d84c49 doc_id: 771734 cord_uid: einxzk0g The fundamental role of microRNAs (miRNAs) has long been associated with regulation of gene expression during transcription and post transcription of mRNA's 3′UTR by the RNA interference mechanism. Also, the process of how miRNAs tend to induce mRNA degradation has been predominantly studied in many infectious diseases. In this article, we would like to discuss the interaction of dietary plant miRNAs derived from fresh fruits against the viral genome of the causative agent of COVID-19, specifically targeting the 3′UTR of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) genome. Expanding the analysis, we have also identified plant miRNAs that interact against the Omicron (B.1.1.529) variant of SARS-CoV-2 across 37 countries/territories throughout the world. This cross-species virus-plant interaction led us to identify the alignment of dietary plant miRNAs found in fruits like Citrus sinensis (Orange), Prunus persica (Peaches), Vitis vinifera (Grapes) and Malus domestica (Apple) onto the viral genomes. In particular, the interaction of C. sinensis miRNA - csi-miR169–3p and SARS-CoV-2 is noteworthy, as the targeted 3′UTR region “CTGCCT” is found conserved amongst all curated 772 Omicron variants across the globe. Hence this site “CTGCCT” and miRNA csi-miR169–3p may become promising therapeutic candidates to induce viral genome silencing. Thereby, this study reveals the mechanistic way of how fruits tend to enact a fight against viruses like SARS-CoV-2 and aid in maintaining a strong immune system of an individual. *** ***** *********** 1. Introduction 1 The world has frequently faced unexpected epidemics caused by viral infections which 2 continue to be a threat for the human population taking its tolls on incalculable lives. The recent 3 events along with many past epidemics express how viral diseases spread rapidly. Throughout the 4 millennium, our planet has witnessed thousands of such outbreaks from the "black death" bubonic 5 plague of the 14th century to the great smallpox pandemic, the yellow fever infection of the 16th 6 century, the 18th century dengue virus fever, followed by the epidemic of Human 7 Immunodeficiency Virus (HIV), and the recent SARS-CoV-2 pandemic [1] . As of 9 th March, 2022, more than 446 million cases of COVID-19 infection were reported, taking 13 toll on 6 million lives worldwide as per WHO statistics [3] . The common symptoms being fever 14 or chills, cough, headache, shortness of breath, muscle or body aches, altered sense of taste or 15 smell, sore throat, congestion, nausea or vomiting, runny nose and even diarrhoea [4] . 16 The starkest emergence is the SARS-CoV-2 related secondary infections of Aspergillus or 17 Rhizopus related Mucormycosis. Also termed as COVID-19 Associated Mucormycosis (CAM) is 18 known to affect those that have a weakened immune system probably due to underlying health 19 comorbidities like diabetes, organ transplantation, or undergoing chemotherapy [5] . The 20 conditions worsened with the onset of the second wave of COVID-19 and the virus continued to 21 evolve showcasing a similar symptom pattern and giving rise to various variants of interests (VOI). Later, on November 26, 2021 an identified mutant strain, known as B.1.1.529, was classified as a 23 variant of concern (VOC) and was named Omicron on the advice of WHO's Technical Advisory 24 Group on Virus Evolution (TAG-VE) [6] . On the current WHO list of VOCs, Omicron joins 25 Alpha, Beta, Gamma and Delta variants of SARS-CoV-2. Omicron seems to have a high number 26 of mutations in its spike protein, which is the primordial target of the host immune response and 27 is also the vaccine target. These mutations are likely to impair the antibodies' capacity to identify 28 the virus and inhibit the viral infection [7] . Apparently, the sharp rise in cases of the Omicron 29 variant in South Africa's Gauteng province is a witness to that. The alarm was set off by the . This serves as the bleak reminder that this war is not yet 5 concluded. 6 As prevention is always a key, all these events advocate that a well-balanced nutritious diet 7 is inevitable for a healthy life. The synergy between balanced diet and nutrition in strengthening 8 the immune system to fight diseases has long been recognized. Nearly 2,500 years ago Hippocrates 9 said, "Let food be thy medicine and medicine be thy food", suggesting that an individual's health 10 status is influenced by both food consumption and disease occurrence [9] . Specific foods or dietary 11 combinations have been known to strengthen the immune system. It's critical to have enough 12 selenium, zinc, iron, and vitamins like A, B 12, B6, C, and E to keep one's immune system healthy 13 [10] . Consequently, dietary habits are important elements of gut microbial composition and, as a 14 result, can influence immune response state of the body [11] . Considering that plants are the 15 primary source of food to many, it is critical to recognise and assess the potential influence of 16 ingested plant miRNAs on host gene expression. 17 miRNAs belong to a class of single-stranded noncoding RNA of approximately 18-23 nucleotides. 18 miRNAs are an integral part of a eukaryotic cell which are responsible for playing a significant 19 part in regulating the gene expression at the post transcriptional level [12] . Most miRNAs are 20 synthesised from DNA sequences as primary miRNAs and then precursor miRNAs and ultimately 21 form mature miRNAs. To disrupt the process of protein translation, miRNAs engage with 3'UTR 22 of target mRNAs to induce translational repression or mRNA destruction to eventually cause 23 miRNA mediated gene silencing [13] . A plant-based diet allows us to absorb the genetic material 24 and nucleic acids that include a considerable amount of plant miRNA. These dietary miRNAs, 25 then enter our body owing a potential to interact with our body's existing nucleic acids. The small 26 miRNAs in fruit when released into the human body, are found to be stable and functional as 27 acidification did not significantly affect the yield and quality of miRNAs. Also, food-derived 8 samples were about one-tenth of that of endogenous miR-16 [14] and when plant RNAs were 1 added directly to food pellets, plant miRNA fragments were also detected in the faeces, GI tract, 2 circulation and reach organs [15] [16] [17] . There are innumerable in vitro evidences which describes 3 the mechanism of action of dietary miRNA and discuss how dietary miRNA are resistant to 4 enzymatic digestion and remain functional. The ingested plant miRNAs remain unaffected by 5 stomach acidification and transit through the gastrointestinal system, enter the bloodstream to 6 reach tissues, for regulating a particular gene expression in mammals and are found to be excreted 7 in urine [14, 18] . The proactive influence of plant miRNA is not just reduced with being an anti-8 viral, but it's also proven to initiate anti-inflammatory, anti-cancer as well as immuno-regulatory 9 affects upon regular consumption of the plant/herb decoction [19] . 10 There is evidence of a plant derived miRNA namely, miRNA2911 obtained from is a repository of biological information and online resources. GenBank is one of the database of 4 NCBI consisting the information and retrieval system for nucleic acid sequences [24] . The 5 reference genome sequence of SARS-CoV-2 was downloaded from NCBI (GenBank accession: individually from the Viridiplantae clade. To find the conserved site availability in other SARS-CoV-2 variants, the related 4 information of VOC and VOI was retrieved from WHO website [6] . The respective genome 5 sequences were downloaded using the 'Pango lineage' keyword search from NCBI as of February 6 The 111 filtered plant miRNA targets were screened on the criteria of 'raw-eatable plants'. biomolecules would lead to build a strong immune system that can withstand the evolving viral 12 attacks [11] . Furthermore, it is interesting to explore the cross-species links of how the pandemic 13 caused by a virus is creating havoc for the mankind and how possibly the immunity provided by 14 food. to a better understanding of their role in plant-human interaction at the molecular level [14] . interact onto the six HBV gene sequences [19] . A report from our study group also revealed a antiviral defence against SARS-CoV-2 infection [23] . These are all amongst the evidence which 10 suggest the conjecture of the inhibitory role of exogenous miRNAs being inhibitory for SARS- 11 CoV-2 viral replication. This work was comprehended with the idea of identifying the conjecture of how 13 consumption of fresh fruits, especially orange fruit on a regular basis can considerably act as a 14 prophylactic in strengthening our immune system or probably as an anti-viral against not just 15 Group on Virus Evolution (TAG-VE) in November 2021 [6] . Plant miRNAs are the initial 17 necessary material and hence mature miRNA sequences were retrieved from miRBase repository. Radius of gyration highlight the overall stability of the nucleotide complex for majority period of 11 the simulation. Furthermore, the conserved site "CTGCCT" comprises a higher percentage of GC 12 content, also seen through the simulation profile and thereby holds a substantial impact on 13 producing a stable interaction with csi-miR169-3p to become a promising target sequence. Availability of data and material 9 The additional data is provided in Supplementary material. 1k 2k 3k 4k 5k 6k 7k 8k 9k 10k 11k 12k 13k 14k 15k 16k 17k 18k 19k 20k 21k 22k 23k 24k 25k 26k 27k 28k 29k eun-miR535b-3p vvi-miR477b-5p ssp-miR444b.1 ppe-miR477-5p csi-miR535d-3p csi-miR535c-3p csi-miR535b-3p csi-miR477a-5p csi-miR482c-3p csi-miR477b-5p csi-miR477d-5p csi-miR477e-5p csi-miR477c-5p csi-miR169c-3p csi-miR169d-3p csi-miR169e-3p mdm-miR477b mdm-miR477a cme-miR477b fve-miR477a Conserved base in Omicron variants of Sars-Cov-2 *********** ******************* ****************** *** ****** ********* * * * * ****** ******************* *************** *** ** *** How pandemics shape social evolution WHO Declares COVID-19 a Pandemic World Health Organization, Coronavirus disease (COVID-19) situation reports in 17 Symptoms of COVID-19 | CDC Omicron (B.1.1.529): Infectivity, vaccine 4 breakthrough, and antibody resistance Heavily mutated Omicron variant puts scientists on alert How Nutrition can help to fight against COVID-19 Pandemic The relationship between nutrition and infectious diseases: 12 A review Optimal nutritional status for a 15 well-functioning immune system is an important factor to protect against viral infections Overview of microRNA biogenesis, 18 mechanisms of actions, and circulation On the importance of host MicroRNAs during viral 21 infection Exogenous plant 25 MIR168a specifically targets mammalian LDLRAP1: Evidence of cross-kingdom 26 regulation by microRNA ScienceDirect The potential 1 atheroprotective role of plant MIR156a as a repressor of monocyte recruitment on 2 inflamed human endothelial cells Stability and absorption mechanism of 5 typical plant miRNAs in an in vitro gastrointestinal environment: basis for their cross-6 kingdom nutritional effects Food-Derived Xeno-microRNAs : Influence of Diet and 10 Detectability in Gastrointestinal Tract -Proof-of-Principle Study SIDT1-dependent absorption in the stomach mediates host uptake of 15 dietary and orally administered microRNAs A Timely 18 Review of Cross-Kingdom Regulation of Plant-Derived MicroRNAs Automated 3D structure composition for large RNAs New functionality of RNAComposer: An application to shape 10 the axis of miR160 precursor structure UCSF Chimera-a visualization system for exploratory research and analysis Gromacs: A parallel 17 computer for molecular dynamics simulations GROMACS: fast, flexible, and free