Severe Acute Respiratory Syndrome Corona Virus -2 (SARS-CoV-2), puzzled the whole world with its diverse, unique clinical spectrum, and unprecedented transmission dynamics. The disease caused by this virus is named as Coronavirus disease-19 (COVID-19), reported first time in Wuhan, China, in December 2019. It had spread to almost all countries of the world disrupting the health and economy of many countries. It was the recent zoonotic spillover disease reported in humans from the Coronavirus group, without proper medicine and non-existence of prior immunity, this disease posed a challenge to both the scientific and medical fraternity. The search for safe, effective drugs to treat the disease and vaccines against the causative agent SARS- CoV-2 had begun all over the world with public and private partnerships. Many countries are part of the solidarity trail for identifying the effective drugs, clinical trials and vaccines for this global pandemic. Here in this review, we are focussing on the different vaccine production platforms being used in the preparation of vaccines against SARS-CoV-2, their current status and prospects. Vaccine production technology significantly advanced in recent times by imbibing the cutting edge technologies such as nucleic acid based technologies such as DNA/RNA/Codon deoptimization and availability of safe and effective viral vectors produced through rDNA technology. The availability of complete genome sequence of SARS-CoV-2, geared up for the production of vaccine candidates based on these new vaccine production platforms, and in a record time of 4-5 months, these vaccine candidates entered in human clinical trials for the evaluation of safety and efficacy. Prior knowledge on SARS and MERS-CoV’s structural and genomic features, vaccine production platforms used in making vaccines against them greatly augmented in the SARS-CoV-2 vaccine efforts. As per World Health Organization (WHO) a total of202 vaccine candidates are under developing for SARS-CoV-2, among them 47 entered in clinical trials and 156 are in the preclinical stage. These vaccines are prepared by an amalgamation of both new and old traditional vaccine production platforms such as nucleic acid base platforms, inactivated, live attenuated, recombinant viral vectors, protein and peptide-based vaccines. The success of these vaccine candidates lies in the generation of effective immune response for SARS-CoV-2 across all age groups and people with co-morbidities. We briefly summarize the different strategies of SARS-CoV-2 vaccine production and their prospects with an emphasis on different routes of administration and added a basic mathematical model depicting the importance of vaccination for any pandemic.
Human Cytomegalovirus (HCMV) is a prototypic beta herpesvirus, causing persistent infections in humans. There are medications that are used to treat the symptoms; however, there is no cure yet. Thus, understanding the molecular mechanisms of HCMV replication and its persistence may reveal new prevention strategies. HCMV evasive strategies on the antiviral responses of the human host largely rely on its significant portion of genome. Numerous studies have highlighted the importance of miRNA-mediated regulation of apoptosis, which is an innate immune mechanism that eradicates virus-infected cells. In this study, we explore the antiapoptotic role of hcmv-miR-UL70-3p in HEK293T cells. We establish that hcmv-miR-UL70-3p targets the proapoptotic gene Modulator of Apoptosis-1 (MOAP1) through interaction with its 3’UTR region of mRNA. The ectopic expression of hcmv-miR-UL70-3p mimic significantly downregulates the H2O2-induced apoptosis through the translational repression of MOAP1. Silencing of MOAP1 through siRNA also inhibits the H2O2-induced apoptosis, which further supports the hcmv-miR-UL70-3p mediated antiapoptotic effect by regulating MOAP1 expression. These results uncover a role for hcmv-miR-UL70-3p and its target MOAP1 in regulating apoptosis.
The propensity of viruses to co-opt host cellular machinery by reprogramming the host’s RNA-interference machinery has been a major focus of research, however, regulation of host defense mechanisms by virus-encoded miRNA, is an additional regulatory realm gaining momentum in the arena of host-viral interactions. The Human Cytomegalovirus (HCMV) miRNAs, regulate many cellular pathways alone or in concordance with HCMV proteins, thereby paving a conducive environment for successful infection in the human host. We show that HCMV miRNA, hcmv-miR-UL148D inhibits staurosporine-induced apoptosis in HEK293T cells. We establish that ERN1 mRNA is a bonafide target of hcmv-miR-UL148D and its encoded protein IRE1α is translationally repressed by the overexpression of hcmv-miR-UL148D resulting in the attenuation of apoptosis. Unlike the host microRNA seed sequence (6–8 nucleotides), hcmv-miR-UL148D has long complementarity to 3’ UTR of ERN1 mRNA resulting in mRNA degradation. The repression of IRE1α by the hcmv-miR-UL148D further downregulates Xbp1 splicing and c-Jun N-terminal kinase phosphorylation thus regulating ER-stress and ER-stress induced apoptotic pathways. Strikingly, depletion of ERN1 attenuates staurosporine-induced apoptosis which further suggests that hcmv-miR-UL148D functions through regulation of its target ERN1. These results uncover a role for hcmv-miR-UL148D and its target ERN1 in regulating ER stress-induced apoptosis.
Human Cytomegalovirus (HCMV), a prototypic member of the Beta-herpesvirinae subfamily, mainly responsible for congenital disabilities in newborns, cause opportunistic infections in immunocompromised individuals. Its seroprevalence varies across the globe ranging from 50–70 percent in developed countries to 90–100 percent in developing countries. Causing latent infections in the immunocompetent host suggests that it employs several strategies to escape the wrath of the host’s antiviral mechanisms. Apoptosis is an innate cellular response to viral infection, and downregulation of this mechanism by HCMV is a well-established phenomenon. HCMV utilizes its proteins, RNA and miRNA in regulating this response to establish a productive infection in the host. The role of HCMV miRNAs on cellular apoptosis is very interesting, where some miRNAs downregulate but a few upregulate this process. In the present study, we report the antiapoptotic activity of HCMV miRNA, miR-UL-70-3p, on H2O2 induced apoptosis in HEK293T cells. The ectopic expression of this HCMV miRNA in HEK293T cells downregulate the apoptosis, and continuing studies reveal that the proapoptotic gene, Modulator of Apoptosis Protein-1 (MOAP1), is a functional target for this miRNA. We verified the functionality of the binding site predicted in the 3'UTR of MOAP1 in our earlier studies through dual luciferase-based assays using both the wild and mutant 3'UTR’s of MOAP1. The MOAP1 protein levels were significantly downregulated by the miR-UL70-3p, suggesting that the MOAP1 mRNA was degraded after binding with the miR-UL70-3p. Further, the extent of MOAP1 mRNA and its protein inhibitions by HCMV miR-UL70-3p and siRNA of MOAP1 were compared and found that the siRNA of MOAP1 inhibits 69.52 percent of mRNA and 35.67 percent of MOAP1 protein; while the miR-UL70-3p inhibits 46.66 percent MOAP1 mRNA and 21.05 percent MOAP1 protein. Though the inhibitory activity of miR-UL70-3p is not equal to the siRNA of MOAP1, but it was significant enough in reversing the H2O2 induced apoptosis in HEK293T cells. These results confirm that hcmv-miR-UL70-3p downregulates H2O2 induced apoptosis in HEK293T cells by targeting the 3'UTR of MOAP1 mRNA.
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