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Neuropathogenesis of viral infections
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Avindra Nath, Joseph R. Berger
Interferons (IFN) are a group of proteins that derive their name from their ability to interfere with viral replication in an indirect fashion. There are three major families of interferons: IFN-α, IFN-β, and IFN-γ. IFN-α and IFN-β have potent antiviral properties within cells exposed to them, whereas IFN-γ enhances the immune system’s ability to clear infected cells mainly after the induction of the adaptive immune response. Therefore, expression of IFN-α and IFN-β early in the course of infection is crucial to preventing the further spread of the virus. IFN-α and IFN-β may become expressed by the presence of a variety of intracellular inducers, including the presence of foreign nucleic acids. In fact, the presence of double-stranded RNA is a potent inducer of their expression. IFN-γ is also important in controlling viral infection even in the absence of other cell mediated immune responses. For example, in measles virus infection, it can clear the virus from infected neurons without causing neuronal cell loss [29]. However, IFN-γ may also inhibit the proliferation of neural progenitor cells and thus affect brain repair and development [30].
Evolution
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Much later, the evolution of tertiary structure of a long list of the viral RNA-dependent polymerases including the Qβ replicase was studied by Černý et al. (2014). The authors stated that the sequence similarity of the enzymes was too low for the phylogenetic studies, although general protein structures were remarkably conserved. The major strength of this work consisted of the unification of the sequence and structural data into a single quantitative phylogenetic analysis, using the powerful Bayesian approach. The resulting phylogram of the enzymes demonstrated that the RNA-dependent DNA polymerases of viruses within the Retroviridae family clustered in a clearly separated group, while the RNA-dependent RNA polymerases of double-stranded and single-stranded RNA viruses were mixed together. This evidence supported the hypothesis that the enzymes replicating the single-stranded RNA viruses evolved multiple times from the enzymes replicating the double-stranded RNA viruses, and vice versa. The authors recommended their phylogram as a scheme for the general RNA virus evolution. This phylogenetic tree of the evolution of the RNA-dependent polymerases and possibly of the RNA viruses is shown in Figure 18.6.
Interferons and their Mechanisms of Action
Published in Velibor Krsmanović, James F. Whitfield, Malignant Cell Secretion, 2019
The nature of the factors which are involved in the induction of IFN by all these microorganisms is not clearly established. Double-stranded RNA (dsRNA) is, however, believed to play a major role, at least in the induction by viruses. A synthetic dsRNA, poly (rI.)poly (rC), is actually one of the most potent inducers of type I interferon. It has been widely used for experimental studies as well as the large-scale production of type I interferons.
Clinical pharmacology of siRNA therapeutics: current status and future prospects
Published in Expert Review of Clinical Pharmacology, 2022
Ahmed Khaled Abosalha, Jacqueline Boyajian, Waqar Ahmad, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash
Simply, siRNAs are designed to block the expression of targeted genes at the post-transcriptional stage by degrading the mRNA that governs the regulation of these genes. Therefore, siRNAs are designated as small double-stranded RNA duplexes with a 21–23 nucleotide length. One strand of this duplex is complementary to the mRNA of the gene of interest and known as the ‘guiding’ or ‘antisense’ strand. This guiding strand can easily and specifically recognize the mRNA of the targeted gene and degrade it, a process known as ‘gene silencing.’ Gene silencing begins when a long double-stranded RNA (dsRNA) is cleaved by a specific dicer enzyme, a member of the RNAase family, into short siRNAs. Then, these siRNAs are incorporated into a multi-protein complex termed, ‘ (RISC).’ Subsequently, siRNA binds to argonaute-2 receptors, a crucial component of RISC, with a consequent cleavage of siRNA duplex into two strands: the passenger (sense) strand and the guiding strand. The sense strand is degraded while the guiding strand recognizes the complementary mRNA of the gene of interest and destroys it into numerous nonfunctional units. This process downregulates the expression of targeted genes and proteins as demonstrated in Figure 1 [29–32].
Efficacy of siRNA-loaded nanoparticles in the treatment of K-RAS mutant lung cancer in vitro
Published in Journal of Microencapsulation, 2022
Ayse Gencer, Ipek Baysal, Emirhan Nemutlu, Samiye Yabanoglu-Ciftci, Betul Arica
The mechanism of the cancer formation is directly or indirectly related to genetic mutations and activation of oncogenes (Heng et al.2010). Gene therapy involves strategies such as repairing, suppressing, or silencing genes that cause cancer formation. The advantage of gene therapy over other treatment approaches is that it is highly specific and suitable for developing individual treatment strategies (Cross and Burmester 2006, Amer 2014). RNA interference is one of the most important genes therapy techniques. It effects through a pathway where double-stranded RNA is attached to the target mRNA of the gene to be silenced and degrades thus, preventing the synthesis of the protein associated with cancer after transcription. For this purpose, small interfering RNA (siRNA) molecules of 20–25 nucleotides length, are obtained by breaking down double stranded RNA (dsRNA) into small RNA fragments by the Dicer enzyme (an RNase III endonuclease which is involved in the biogenesis of small RNAs) are used (Song and Rossi 2017). After the transfection of siRNA into cells via different transfection methods, it forms a complex with RNA-Induced Silencing Complex (RISC) containing endonuclease, exonuclease, and helicase enzymes in its structure. This complex binds to target mRNA by recognise it through the siRNA. As a result, the mRNA is degraded and inactivated by RISC (Devi 2006, Rao et al.2013, Mansoori et al.2014).
Back to basics: review on vitamin D and respiratory viral infections including COVID-19
Published in Journal of Community Hospital Internal Medicine Perspectives, 2020
Mamtha Balla, Ganesh Prasad Merugu, Venu Madhav Konala, Vikram Sangani, Hema Kondakindi, Mytri Pokal, Vijay Gayam, Sreedhar Adapa, Srikanth Naramala, Srikrishna V Malayala
Vitamin D shows its effect on both adaptive and innate immune responses. Various in vitro studies showed that 1, 25 (OH) D affected the development of Th1 mediated immunity by inhibiting it, which is essential for cellular response induction. Cytokines that are dependent on the activity of nuclear factor κB (NF-κB) in multiple cells, including macrophages, by blocking the activation of NF-κB p65 through upregulation of the NF-kB inhibitory protein 1κBα are also directly modulated by 1,25 (OH)2 D[16]. Toll-like receptors (TLRs) are transmembrane proteins that recognize molecular motifs of viral and bacterial origin and initiate innate immune responses. TLR3, which is mainly involved in defense against viruses, recognizes viral double-stranded RNA. The treatment with Vitamin D has shown to reduce double-stranded RNA-TLR3–induced expression of IL-8 in respiratory epithelial cells[12]. Both 25 (OH) D and 1, 25 (OH)2 D were shown to modulate T-cell adaptive immunity. The mechanism is by decreasing the pro-inflammatory type 1 cytokines such as IL-6, IL-8, IL-12, IFN-γ, as well as IL-17 and tumor necrosis factor-α) and also by increasing regulatory T cells and anti-inflammatory type 2 cytokines such as IL-4, IL-5, and IL-10 [17–19]. In the summer months, reduction in the pro-inflammatory levels of IL-1, IL-6, TNF-α, IFN-γ, and IL-10 are observed on TLR stimulation of human peripheral blood mononuclear cells when compared to the winter where the respiratory viral infections are at its peak[20].