Interferons (IFNs) are widely used in treating coronavirus disease 2019 (COVID-19) patients. However, a recent report of ACE2, the host factor mediating SARS-Cov-2 infection, identifying it as interferon-stimulated raised considerable safety concern. To examine the association between the use and timing of IFN-α2b and clinical outcomes, we analyzed in a retrospective multicenter cohort study of 446 COVID-19 patients in Hubei, China. Regression models estimated that early administration (≤5 days after admission) of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality. Among survivors, early IFN-α2b was not associated with hospital discharge or computed tomography (CT) scan improvement, whereas late IFN-α2b was associated with delayed recovery. Additionally, early IFN-α2b and umifenovir alone or together were associated with reduced mortality and accelerated recovery in comparison with treatment with lopinavir/ritonavir (LPV/r) alone. We concluded that administration of IFN-α2b during the early stage of COVID-19 could induce favorable clinical responses.
Internal N 6 -methyladenosine (m 6 A) modification is one of the most common and abundant modifications of RNA. However, the biological role(s) of viral RNA m 6 A remains elusive. Using human metapneumovirus (hMPV) as a model, we demonstrate that m 6 A serves as a molecular marker for innate immune discrimination of self from nonself RNAs. We show that hMPV RNAs are m 6 A methylated and that viral m 6 A methylation promotes hMPV replication and gene expression. Inactivating m 6 A addition sites with synonymous mutations or demethylase resulted in m 6 A deficient recombinant hMPVs and virion RNAs that induced significantly higher expression of type I interferon (IFN) which was dependent on the cytoplasmic RNA sensor RIG-I, not MDA5. Mechanistically, m 6 A-deficient virion RNA induces higher expression of RIG-I, binds more efficiently to RIG-I, and facilitates the conformational change of RIG-I, leading to enhanced IFN expression. Furthermore, m 6 A-deficient rhMPVs triggered higher IFN in vivo and were significantly attenuated in cotton rats yet retained high immunogenicity. Collectively, our results highlight that (i) virus acquires m 6 A in their RNAs as a means of mimicking cellular RNA to avoid detection by innate immunity; and (ii) viral RNA m 6 A can serve as a target to attenuate hMPV for vaccine purposes.
N6-methyladenosine (m6A) is the most prevalent internal modification of mRNAs in most eukaryotes. Here we show that RNAs of human respiratory syncytial virus (RSV) are modified by m6A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of m6A methyltransferases decreases RSV replication and gene expression whereas knockdown of m6A demethylases has the opposite effect. The G gene transcript contains the most m6A modifications. Recombinant RSV variants expressing G transcripts that lack particular clusters of m6A display reduced replication in A549 cells, primary well differentiated human airway epithelial cultures, and respiratory tracts of cotton rats. One of the m6A-deficient variants is highly attenuated yet retains high immunogenicity in cotton rats. Collectively, our results demonstrate that viral m6A methylation upregulates RSV replication and pathogenesis and identify viral m6A methylation as a target for rational design of live attenuated vaccine candidates for RSV and perhaps other pneumoviruses.
Cuproptosis, a newly identified form of regulated cell death that is copper‐dependent, offers great opportunities for exploring the use of copper‐based nanomaterials inducing cuproptosis for cancer treatment. Here, a glucose oxidase (GOx)‐engineered nonporous copper(I) 1,2,4‐triazolate ([Cu(tz)]) coordination polymer (CP) nanoplatform, denoted as GOx@[Cu(tz)], for starvation‐augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be “turned on” for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@[Cu(tz)]‐mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper‐induced toxicity. The increased intracellular hydrogen peroxide (H2O2) levels, due to the oxidation of glucose, activates the type I photodynamic therapy (PDT) efficacy of GOx@[Cu(tz)]. The in vivo experimental results indicate that GOx@[Cu(tz)] produces negligible systemic toxicity and inhibits tumor growth by 92.4% in athymic mice bearing 5637 bladder tumors. This is thought to be the first report of a cupreous nanomaterial capable of inducing cuproptosis and cuproptosis‐based synergistic therapy in bladder cancer, which should invigorate studies pursuing rational design of efficacious cancer therapy strategies based on cuproptosis.
In article number 1601691, Y. Zhang and G. Wittstock demonstrate a novel and powerful platform for manipulation of microdroplets based on controlling the adhesion work to a hydrophobic wire. The wire can be used to pick up, transport, and lay down droplets with volumes between picoliters to microliters, avoiding the sliding of droplets over chip surfaces. Tissue Engineering In article number 1602769, H. Yu, L. Liu, and co-workers demonstrate a Tetris-inspired approach to fabricate 3D heterogeneous microscale tissue from hydrogel building blocks. The investigated system combines optofluidic maskless lithography and optically induced dielectrophoresis (ODEP). The customized bio-microstructures in Tetris shapes are dynamically synthesized using an optofluidic maskless lithography system and then transferred to an optically induced electrokinetics (OEK) chip for manipulation and assembly. Tumor Visualization Anaerobic Clostridium novyi-NT (C. novyi-NT) has proved to be effective for treating tumors. X-ray computed tomography (CT) image guided delivery of this strain of bacteria to tumors has several great advantages over previous methods. In article number 1602722, A. C. Larson, D.-H. Kim, and co-workers developed an approach to coat the surface of C. novyi-NT spores with gold nanoparticles for CT-guided bacteriolytic therapy. Branched gold nanoparticles-coated spores are successfully injected into a tumor site under CT image guidance. A strong anti-tumor effect was observed in the in vivo tumor model.
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