key: cord-0947932-6hvckncv authors: Vadivalagan, Chithravel; Shitu, Anushka; Kamalakannan, Siva; Chen, Ruei-Ming; Serrano-Aroca, Ángel; Mishra, Vijay; Aljabali, Alaa A.A.; Singh, Sachin Kumar; Chellappan, Dinesh Kumar; Gupta, Gaurav; Dua, Kamal; El-Tanani, Mohamed; Tambuwala, Murtaza M.; Krishnan, Anand title: Exosomal mediated signal transduction through artificial microRNA (amiRNA): A potential target for inhibition of SARS-CoV-2 date: 2022-04-21 journal: Cell Signal DOI: 10.1016/j.cellsig.2022.110334 sha: 0d0f7bc51ca1870b82384b2593014aa7d33d3e1f doc_id: 947932 cord_uid: 6hvckncv Exosome trans-membrane signals provide cellular communication between the cells through transport and/or receiving the signal by molecule, change the functional metabolism, and stimulate and/or inhibit receptor signal complexes. COVID19 genetic transformations are varied in different geographic positions, and single nucleotide polymorphic lineages were reported in the second waves due to the fast mutational rate and adaptation. Several vaccines were developed and in treatment practice, but effective control has yet to reach in cent presence. It was initially a narrow immune-modulating protein target. Controlling these diverse viral strains may inhibit their transuding mechanisms primarily to target RNA genes responsible for COVID19 transcription. Exosomal miRNAs are the main sources of transmembrane signals, and trans-located miRNAs can directly target COVID19 mRNA transcription. This review discussed targeted viral transcription by delivering the artificial miRNA (amiRNA) mediated exosomes in the infected cells and significant resources of exosome and their efficacy. The COVID19 variants are the most important issue for vaccine development; perhaps different mutants have been reposted in recent days and countries representing new mutants, especially the UK, USA, Nigeria, South Africa, and India. Currently, several vaccines are performing against COVID19, but strains variations are intense to less effective and need alternatives [1] . Exosomes act as vesicular cargo which carries signaling molecules, enzymes for a metabolic task, nanomolecular disposal, and they can provide mono and bidirectional functions by cellular conversations [2] . miRNAs are being used as a platform for live attenuated DNA vaccines, and it also manipulates the host endogenous RNA viruses by providing both positive and negative senses [3] . Exosomal miRNAs utilize therapeutic approaches [4] and are considered unique biomarkers for targeted gene therapy [5] . Based on characteristic approaches, inactivation and inhibition of miRNA-based therapeutics tactics are reported, and specific miRNAs are accountable for the immune response against COVID19 people residing near the location or due to indulgence in the wildlife trade of infected animals [4] . The virus interacts with humans due to its survival, development, and distribution: the second stage, viral exposure, route of entry, and dose of virus. The last stage is influenced by genetic factors, the physiological and immunological status of the human host. These last two factors determine the possibility and severity of infection [12] . SARS is an airborne virus, transmitted via as cold and flu do. The virus spreads by an infected person coughing or sneezing, leaving small droplets in the air or stool. So, the person who inhales such droplets or touches the infected surfaces may also get infected [106, 107] . Reports state that the receptor-binding domain (RBD) of virus spikes binds to the ACE2 receptor of the potential host cell in the case of human-to-human transmission [16, 17] . The most exciting feature is that SARS-CoV-2 and SARS-CoV spikes share RBD sequence similarity, strongly suggesting their standard entry route into the host cells via the ACE2 receptor [17]. They have also been used to treat several influenza-like viruses, including H5N1. While these are rather different from SARS-COV2, the basic mechanism of action for both the viruses is the same. While the signal transduction pathways are different, miRNA involvement due to the initial protein synthesis can be inhibited in both cases. Convalescent plasma, already known for treating SARS-CoV2 infection [107] can undoubtedly be used to isolate exosomes, which likely play a significant role in the prognosis of the disease. Meanwhile, blood plasma contains several cells that can be used to isolate exosomes. In order to target a virus, it is essential to look at sources from the immune system as these are The strategy the virus needs to develop is first to fuse itself within the host's cell membrane and induce host cell-cell fusion. This process is called endocytosis invasion of neighbour cell membrane so-called syncytium [60] . Syncytium formation leading to the creation of giant multinucleated cells in the placenta makes this tissue impermeable and generates mother-child immune tolerance [61] . Syncytin genes are hypomethylated and therefore functionally active in the mammalian placenta, whereas they are hypermethylated and thus silenced in other tissues, where syncytium formation may cause various diseases, i.e., schizophrenia, multiple sclerosis, and diabetes type 1 [62] . CpG methylation of syncytin genes in non-placental tissues is obligatory for preventing the expression of syncytiumforming proteins [63] . Several viruses use the human syncytin genes to fuse themselves with 21 miR-5197-3p therapeutic potential, since they bind with viral COVID 19 [79] J o u r n a l P r e -p r o o f HBV related hepatocellular carcinoma [82] 26 hsa-miR- Linked to the occurrence of glioblastoma Cancer [83] J o u r n a l P r e -p r o o f Plays a role in cell growth and proliferation through the ornithine decarboxylase pathway Ovarian cancer [84] 28 hsa-miR- Plays a role in the regulation of several cellular processes through regulation of production of nfk-beta glioblastoma [85] J o u r n a l P r e -p r o o f Journal Pre-proof After the virus enters the body through droplet inhalation, they attach to specific host cells through adhesion to ACE-2, beginning the infection cycle as was discussed above [86] . The primary process which we want to target is that of virus transformation. The SARS-CoV 2 transformation in the human model has been studied in vivo conditions and can certainly be used to develop therapeutic solutions to the infection [87] . Although the strains rapidly mutated through different factors that cause spike protein changes and nucleocapsid, the infection pattern remains the same [88]. Hence, our treatment strategy is to target the host factors that contribute to the transmission of the virus, mainly focusing on viral transformation. The molecule of interest for this study is miRNA, which is responsible for gene silencing at the transcriptional, translation, and epigenetic levels [89] . Our study used to screen the miRNA involved in the viral transduction process from convalescent plasmaderived exosomes instead of those from the immune due to their high potency. This miRNA can be identified through the transcriptome analysis of potential target genes to understand viral transduction mechanisms. This selected miRNA can be synthesized and encapsulated with exosomes derived from mesenchymal stem cells. However, the ideal state of the exosomes will be nonspecific, so that any cargo can be loaded into it [90] . Additionally, a source with abundant exosomes would be required for this process. Exosomes isolated from mesenchymal stem cells would undoubtedly be suitable [09] . As mesenchymal stem cells are crucial for the establishment of most microenvironments, they contain a significant number of empty exosomes to be filled with cargo during differentiation [91] . Although certainly efficient for immunotherapy, any other immune-derived exosomes or those isolated from convalescent plasma would not be ideal for transferring miRNA. The To determine the specific miRNA which can be used to arrest the viral infection, a detailed study of the process and the host genes involved is essential. The one pathway in which transcription factors were up-regulated in response to nucleocapsid entry was that of the AP1 transcription factor complex. The pathway is involved in several processes, including induction of apoptosis, cytokine production, and bacterial and viral infections [92] . Meanwhile, it also targets PTEN and AKT-3, which can be used to inhibit the PI3K pathway. Similarly, the SMAD4 gene could be inhibited to stop the TGF-beta signaling pathway [102] . The Wnt pathway can also be targeted through Wnt-3 is another proliferative pathway [103] . These are the cytoplasmic pathways that could be targeted, the last step being the inhibition of CREB1, preventing the process of viral transduction [104] . Several general pathways can be regulated with the help of miR190a-3p. This is the most important pathway, occurring within the nucleus, the AP-1 pathway. This is the point for transcriptional inhibition, where the viral transduction can be inhibited [105] . Hence the study focuses on transcriptional inhibition of viral transduction through artificial miRNA to target mRNA or gene. system of miRNA to infected cells. Inhibition of transcription of the target gene mRNA through artificially synthesized miRNA will block the AP-1 pathway responsible for spread by blocking the target gene CREB1. The goal is to arrest the process of viral transduction. This approach does not involve fighting against the immune response but combating the spread of the virions to other infected cells. The proposition is not a treatment method but can be an approach to stop the spread of the infection. The principle in this study can be applied to treat any infected cells in any part of the body and for any viral infection. Arresting the transduction process can be a new approach to dealing with viral infections. The use of exosomes to deliver artificial miRNA can be an efficient protocol for controlling the spread of the viral infection through the body, minimizing the damage to the patient's health. 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A preliminary report Authors declare no conflict of interest regarding any financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work.