Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread worldwide and has affected more than 10 million individuals. A typical feature of COVID-19 is the suppression of type I and III interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive. Here, we reported that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling. In addition, the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1, thus preventing the formation of the multiprotein complex containing RIG-I, MAVS, TRAF3, and TBK1 and subsequently impeding the phosphorylation, nuclear translocation, and activation of IRF3. Consequently, ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus. Taken together, these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.
The suppression of types I and III interferon (IFN) responses by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) contributes to the pathogenesis of coronavirus disease 2019 (COVID‐19). The strategy used by SARS‐CoV‐2 to evade antiviral immunity needs further investigation. Here, we reported that SARS‐CoV‐2 ORF9b inhibited types I and III IFN production by targeting multiple molecules of innate antiviral signaling pathways. SARS‐CoV‐2 ORF9b impaired the induction of types I and III IFNs by Sendai virus and poly (I:C). SARS‐CoV‐2 ORF9b inhibited the activation of types I and III IFNs induced by the components of cytosolic dsRNA‐sensing pathways of RIG‐I/MDA5‐MAVS signaling, including RIG‐I, MDA‐5, MAVS, TBK1, and IKKε, rather than IRF3‐5D, which is the active form of IRF3. SARS‐CoV‐2 ORF9b also suppressed the induction of types I and III IFNs by TRIF and STING, which are the adaptor protein of the endosome RNA‐sensing pathway of TLR3‐TRIF signaling and the adaptor protein of the cytosolic DNA‐sensing pathway of cGAS–STING signaling, respectively. A mechanistic analysis revealed that the SARS‐CoV‐2 ORF9b protein interacted with RIG‐I, MDA‐5, MAVS, TRIF, STING, and TBK1 and impeded the phosphorylation and nuclear translocation of IRF3. In addition, SARS‐CoV‐2 ORF9b facilitated the replication of the vesicular stomatitis virus. Therefore, the results showed that SARS‐CoV‐2 ORF9b negatively regulates antiviral immunity and thus facilitates viral replication. This study contributes to our understanding of the molecular mechanism through which SARS‐CoV‐2 impairs antiviral immunity and provides an essential clue to the pathogenesis of COVID‐19.
In this work, chemiluminescence (CL) reagent and catalyst metal ion complexes bifunctionalized gold nanoparticles (BF-AuNPs) with high CL efficiency were synthesized via an improved synthesis strategy. Biothiols, such as cysteine (Cys), cysteinyl-glycine (Cys-Gly), homocysteine (Hcy), and glutathione (GSH), instead of 2-[bis[2-[carboxymethyl-[2-oxo-2-(2-sulfanylethylamino)ethyl]amino]ethyl]amino]acetic acid (DTDTPA), were used as new chelators. N-(aminobutyl)-N-(ethylisoluminol) (ABEI) was used as a model of CL reagents and Cu(2+) as a model of metal ion. In this strategy, biothiols were first grafted on the surface of ABEI-AuNPs by Au-S bond. Then, Cu(2+) was captured onto the surface of ABEI-AuNPs by the coordination reaction to form BF-AuNPs. The CL intensity of Cu(2+)-Cys/ABEI-AuNPs was 1 order of magnitude higher than that of DTDTPA/Cu(2+)-ABEI-AuNPs synthesized by the previous work. Moreover, strong CL emission of Cu(2+)-Cys/ABEI-AuNPs was also observed in neutral pH conditions. In addition, the present BF-AuNPs synthesis method exhibited advantages over the previous method in CL efficiency, simplicity, and synthetic rate. Finally, by virtue of Cu(2+)-Cys/ABEI-AuNPs as a platform, a simple CL chemosensor for the sensitive and selective detection of pyrophosphate ion (PPi) was established based on the competitive coordination interactions of Cu(2+) between Cys and PPi. The method exhibited a wide detection range from 10 nM to 100 μM, with a low detection limit of 3.6 nM. The chemosensor was successfully applied to the detection of PPi in human plasma samples. It is of great application potential in clinical analysis. This work reveals that BF-AuNPs could be used as ideal nanointerface for the development of novel analytical methods.
Bacteria use surface appendages called type IV pili to perform diverse activities including DNA uptake, twitching motility, and attachment to surfaces. The dynamic extension and retraction of pili are often required for these activities, but the stimuli that regulate these dynamics remain poorly characterized. To address this question, we study the bacterial pathogen Vibrio cholerae, which uses mannose-sensitive hemagglutinin (MSHA) pili to attach to surfaces in aquatic environments as the first step in biofilm formation. Here, we use a combination of genetic and cell biological approaches to describe a regulatory pathway that allows V. cholerae to rapidly abort biofilm formation. Specifically, we show that V. cholerae cells retract MSHA pili and detach from a surface in a diffusion-limited, enclosed environment. This response is dependent on the phosphodiesterase CdpA, which decreases intracellular levels of cyclic-di-GMP to induce MSHA pilus retraction. CdpA contains a putative nitric oxide (NO)–sensing NosP domain, and we demonstrate that NO is necessary and sufficient to stimulate CdpA-dependent detachment. Thus, we hypothesize that the endogenous production of NO (or an NO-like molecule) in V. cholerae stimulates the retraction of MSHA pili. These results extend our understanding of how environmental cues can be integrated into the complex regulatory pathways that control pilus dynamic activity and attachment in bacterial species.
Difluoroboron β-diketonates (BF bdks) show both fluorescence (F) and room-temperature phosphorescence (RTP) when confined to a rigid matrix, such as poly(lactic acid). These materials have been utilized as optical oxygen sensors (e.g., in tumors, wounds, and cells). Spectral features include charge transfer (CT) from the major aromatic donor to the dioxaborine acceptor. A series of naphthyl-phenyl dyes (BF nbm) (1-6) were prepared to test heavy-atom placement effects. The BF nbm dye (1) was substituted with Br on naphthyl (2), phenyl (3), or both rings (4) to tailor the fluorescence/phosphorescence ratio and RTP lifetime-important features for designing O sensing dyes by means of the heavy atom effect. Computational studies identify the naphthyl ring as the major donor. Thus, Br substitution on the naphthyl ring produced greater effects on the optical properties, such as increased RTP intensity and decreased RTP lifetime compared to phenyl substitution. However, for electron-donating piperidyl-phenyl dyes (5), the phenyl aromatic is the major donor. As a result, Br substitution on the naphthyl ring (6) did not alter the optical properties significantly. Experimental data and computational modeling show the importance of Br position. The S and T states are described by two singly occupied MOs (SOMOs). When both of these SOMOs have substantial amplitude on the heavy atom, passage from S to T and emission from T to S are both favored. This shortens the excited-state lifetimes and enhances phosphorescence.
Owing to their facile
synthesis and desirable optical properties,
β-diketones (bdks) are attractive scaffolds for the production
of new mechanochromic luminescent (ML) materials. However, ML-active
bdk dyes that can access full color luminescent states (i.e., red,
green, and blue) have yet to be realized. To synthesize such a set
of bdk emitters, two strategies were used to red-shift the emission:
substitution with varying donor and acceptor groups; and coordination
of BF2 to the β-diketonate moiety. Additionally,
3,4,5-trimethoxy-substituted phenyl rings were used to disrupt the
molecular packing to promote ML and enable aggregation-induced emission
(AIE). Here, a series of trimethoxy-substituted bdks were prepared
via Claisen condensation, each para-substituted with either F, I,
or CN groups. Their boronated complexes were synthesized via reaction
with boron trifluoride diethyl etherate. Optimized geometries generated
from density functional theory calculations indicated that the dye
para-substituted methoxy groups were directed out of the molecular
plane, potentially leading to loose solid-state packing. The AIE studies
using tetrahydrofuran/H2O solutions indicated AIE activity
in both bdk dyes and boron complexes. High-contrast ML was also observed
for each dye investigated. Furthermore, this set of dyes exhibited
emissions crossing the entire visible spectrum, thereby demonstrating
a strategy for color tuning and promoting ML and AIE in bdk systems.
The as-prepared CoII(HQS)2/ABEI/rGO hybrids exhibited excellent CL activity when reacted with hydrogen peroxide, the dissolved oxygen and periodate in alkaline solution.
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