Molecular Therapy — Nucleic Acids, Год журнала: 2022, Номер 30, С. 270 - 271

Опубликована: Окт. 19, 2022

The human immune system can detect the presence of foreign double-stranded RNA (dsRNAs) and activates innate response against viral invaders by boosting secretion cytokines called interferons (IFN). In this issue, Si et al. have found a new class immunostimulatory dsRNAs that potently promote production two kinds IFN (IFN-I IFN-III) while reducing inflammation often observed with known types immunostimulants.1Si L. Bai H. Oh C.Y. Jiang A. Hong F. Zhang T. Ye Y. Jordan T.X. Logue J. McGrath M. al.Self-assembling short duplex RNAs broad-spectrum antiviral activity.Mol. Ther. Nucleic Acids. 2022; 29: 923-940Abstract Full Text PDF PubMed Scopus (3) Google Scholar When dsRNA molecules were tested in traditional cell culture as well complexed Human Organ Chip model lung faithfully mimics its vivo counterpart, they inhibited infection many viruses pandemic potential, such SARS-CoV, SARS-CoV-2, MERS-CoV, various influenza A strains. mouse COVID-19, decreased virus more than 1,000-fold. This technology has potential to become broadly applied approach for combating future pandemics. discovery was made inadvertently when interfering (siRNA) sequences developed "knock down" host genes determine how affected infection. researchers discovered mixture three siRNAs prevented cells 90% lowered gene named DGCR5 80%. However, subsequent analysis revealed effect side siRNA not direct DGCR5. specific sequence, which is 25–27 nucleotides, induced overexpression numerous involved signaling pathway. particularly noteworthy due fact employing purposefully devoid recognized immune-stimulating structural characteristics. Additional study indicated particular exclusively triggered RIG-I pathway, but other downstream pathways (TLR3 or MDA5). To better understand mechanism action type previously unidentified RNA, 200 then generated tease out what driving stimulation. They identified nucleotide sequence motif, occurred on ends similar high activity: cytosine (C) one strand guanines (GGG) strand. motif's position within molecule modified, lost their effects, confirming it crucial element activation. Because C GGG elements motif are different lengths, end each an "overhang" guanines. copies present, four these bind via unusual phenomenon G-G Hoogsteen base pairing. resulting dimers effectively, causing efficacy newly living cells, pitted them poly (I:C), widely used immunostimulant activate cellular sensors, including TLR3, RIG-I, MDA5. administered epithelial produced restricted, less inflammatory response, whereas (I:C) caused far larger changes expression biological processes needed normal function. Subsequently, team Lung Airway Alveolus replicate function responses infections vitro.2Bai Belgur C. Zhai Plebani R. Rodas Patil Nurani al.Mechanical control alveolus chip.Nat. Commun. 13: 1928Crossref (24) Scholar,3Bai Ingber D.E. What organ-on-a-chip teach us about pathophysiology?.Physiology. 37: 000Crossref (5) Scholar,4Si Cao W. Moller Hoagland D. Oishi K. Horiuchi S. al.A human-airway-on-a-chip rapid identification candidate therapeutics prophylactics.Nat. Biomed. Eng. 2021; 5: 815-829Crossref (156) transfected into healthy chips saw 12- 40-fold increase IFN-beta expression. injected organ chips, 80%–90%. COVID-19 evident we need therapies attenuate wide range viruses, rather designing tailored therapy illness emerges. So, related coronaviruses HCoV-NL63. mammalian line, MERS-CoV HCoV-NL63 90%, SARS-CoV Furthermore, SARS-CoV-2 lines 99.99%. Finally, evaluated COVID-19. mice infected burden factor 1,000 delivered intravenously. addition treating infections, treat bacterial, fungal, parasite diseases cancer could benefit from production. Additionally, be employed adjuvant boost vaccinations. research required identify best time treatment, activating too late may aggravate inflammation. Better routes delivering reduce systemic activation., example, directly upper airway, also translate treatment.

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