Inherited deficiency of the OAS-RNase L pathway in children with MIS-C

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Consistent with the absence of pneumonia in these patients, epithelial cells and fibroblasts defective for this pathway restricted SARS-CoV-2 normally. This contrasted with IFNAR1-deficient cells from patients prone to hypoxemic pneumonia without MIS-C. Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV- 2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-but not RNase L- deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.Copyright © 2023 Elsevier Inc.

Cordycepin and its Nucleoside Analogs for the Treatment of Systemic COVID-19 Infection

Coronavirus disease (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus isolated from Wuhan, China. It is a global health emergency, and there is no effective antiviral therapeutics available to date. Continuous structural genomic insights of SARS-CoV-2 proteins provide a warranty for the development of ra-tional-based antivirals. Nevertheless, a structure-based drug candidate with multiple therapeutic actions would be a practical choice of medication in the treatment of severe COVID-19 patients. Cordycepin from medicinal fungi (Cordyceps spp.) and its nucleoside analogs targeting viral RNA-dependent RNA polymerase and human RNase L have potent antiviral activity against various human viruses with additional immunomodulatory and anti-inflammatory effects. Anti-inflammation treatment is of pivotal importance and should be timely tailored to the individual patient along with antivirals. Our perspective on the combined antiviral and anti-inflammatory effects of cordycepin and its analogs suggests them as new therapeutics in the treatment of systemic COVID-19 infec-tion.Copyright © 2022 Bentham Science Publishers.

Candidates-biomarkers for the express testsystem to diagnosis of SARS-CoV-2-induced immunopathology

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for an ongoing global COVID- 19 pandemic. The clinical course of COVID-19 varies from mild symptoms to acute respiratory distress syndrome, hyperinflammation, and coagulation disorder. Gene expression analysis in peripheral blood cells (PBCs) is valuable to evaluate disease-associated and drug-response related genes. In this study, we aimed to investigate the gene expression profile of PBCs in patients with COVID-19. Whole blood samples were collected from patients with acute COVID-19 infection (n = 52) and healthy volunteers (n = 59). The gene expression of PBCs was determined by RTqPCR. We investigated the expression of cytokines, interferonstimulated, CD4, and coagulation genes in PBCs of the infected and healthy samples. Hyperexpression mRNA level of the OAS1, RNASEL, MX1, EIE2AK2, IL8, IL6, IL10, F5 was found out in the blood of SARS-CoV-2-infected patients compared to the healthy sample. We also studied downexpression mRNA level of CD4 in PBCs of SARS-CoV-2-infected patients compared to the healthy volunteers. We have identified the OAS1, RNASEL, MX1, EIE2AK2, IL8, IL6, IL10, F5, CD4 genes in whole blood that classifies SARS-CoV-2-infected and healthy patients with good accuracy. Using the ROC curve we found out that F5, MX1, RNASEL, CD4, IL10, EIF2AK2 genes are promising ?andidates- biomarkers for the express test-system to early diagnosis of COVID-19 immunopathologies (hyperinflammation, coagulation disorders, lymphopenia). These results suggested that the expression of cytokines, coagulation, CD4, interferon-stimulated genes in PBCs can be used for early detection of hyperinflammation, coagulation disorders, lymphopenia at COVID-19, and evaluation of efficiency treatment of this disease.

Efficient Inhibition of SARS-CoV-2 Using Chimeric Antisense Oligonucleotides through RNase L Activation*.

There is an urgent need to develop antiviral drugs and alleviate the current COVID-19 pandemic. Herein we report the design and construction of chimeric oligonucleotides comprising a 2'-OMe-modified antisense oligonucleotide and a 5'-phosphorylated 2'-5' poly(A)4 (4A2-5 ) to degrade envelope and spike RNAs of SARS-CoV-2. The oligonucleotide was used for searching and recognizing target viral RNA sequence, and the conjugated 4A2-5 was used for guided RNase L activation to sequence-specifically degrade viral RNAs. Since RNase L can potently cleave single-stranded RNA during innate antiviral response, degradation efficiencies with these chimeras were twice as much as those with only antisense oligonucleotides for both SARS-CoV-2 RNA targets. In pseudovirus infection models, chimera-S4 achieved potent and broad-spectrum inhibition of SARS-CoV-2 and its N501Y and/or ΔH69/ΔV70 mutants, indicating a promising antiviral agent based on the nucleic acid-hydrolysis targeting chimera (NATAC) strategy.