[Abstract unavailable

The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-β promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-β treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.

The Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily is important in differentially recognizing pathogen products and eliciting appropriate immune responses. These receptors alter gene expression, mainly through the activation of nuclear factor-kappaB and activating protein 1. SIGIRR (single immunoglobulin IL-1R-related molecule), a member of this family that does not activate these factors, instead negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-deficient mice showed enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling.

No abstract

Enterovirus 71 (EV71) is the major causative pathogen of hand, foot, and mouth disease (HFMD). Its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. Strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether EV71 evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins. Here, we show that EV71 inhibits anti-viral type I interferon (IFN) responses by targeting the mitochondrial anti-viral signaling (MAVS) protein—a unique adaptor molecule activated upon retinoic acid induced gene-I (RIG-I) and melanoma differentiation associated gene (MDA-5) viral recognition receptor signaling—upstream of type I interferon production. MAVS was cleaved and released from mitochondria during EV71 infection. An in vitro cleavage assay demonstrated that the viral 2A protease (2Apro), but not the mutant 2Apro (2Apro-110) containing an inactivated catalytic site, cleaved MAVS. The Protease-Glo assay revealed that MAVS was cleaved at 3 residues between the proline-rich and transmembrane domains, and the resulting fragmentation effectively inactivated downstream signaling. In addition to MAVS cleavage, we found that EV71 infection also induced morphologic and functional changes to the mitochondria. The EV71 structural protein VP1 was detected on purified mitochondria, suggesting not only a novel role for mitochondria in the EV71 replication cycle but also an explanation of how EV71-derived 2Apro could approach MAVS. Taken together, our findings reveal a novel strategy employed by EV71 to escape host anti-viral innate immunity that complements the known EV71-mediated immune-evasion mechanisms.

Structure of EV71 2C unveils the structural basis of the functional mechanism of carboxyl terminus–mediated self-oligomerization.

No abstract

Innate immunity provides the first line of host defense against invading microbial pathogens. This defense involves retinoic acidinducible gene-I-like receptors that detect viral RNA and activate the mitochondrial antiviral-signaling (MAVS) protein, an adaptor protein, leading to activation of the innate antiviral immune response. The mechanisms by which the MAVS signalosome assembles on mitochondria are only partially understood. Here, we identify tripartite motif 14 (TRIM14) as a mediator in the immune response against viral infection. TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63-linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3 and NF-κB pathways. Knockdown of TRIM14 disrupts the association between NF-κB essential modulator and MAVS and attenuates the antiviral response. Our results indicate that TRIM14 is a component of the mitochondrial antiviral immunity that facilitates the immune response mediated by retinoic acidinducible gene-I-like receptors.A ctivation of the innate immune response involves the detection of pathogen-associated molecular patterns (PAMPs), such as microbial nucleic acids, proteins, lipids, and carbohydrates. PAMPs are recognized by cellular pattern recognition receptors (PRRs), including Toll-like receptors, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors, and C-type lectin receptors. Upon recognition, PRRs trigger a series of signaling events that lead to the induction of type I IFNs and proinflammatory cytokines (1).RLRs such as RIG-I and melanoma differentiation-associated antigen 5 (MDA5) recognize cytosolic viral RNA (2). Upon binding of RNA to the helicase domain, RIG-I or MDA5 undergoes a conformational change (3) and is recruited to the mitochondrial antiviral signaling (MAVS) adaptor. After binding of RIG-1 or MAD5, MAVS recruits various downstream molecules and further activates two kinase complexes: the noncanonical IκB kinases (IKKs) [TANK-binding kinase 1 (TBK1)/IKKi] and the canonical IKK complexes comprised of IKKα, IKK-β, and NF-κB essential modulator (NEMO) (4, 5). The TBK1/IKKi kinases phosphorylate IFN regulatory factor 3/7 (IRF3/7), which translocates to the nucleus and drives the transcription of IFNs (6). The canonical IKKs phosphorylate IκBα, resulting in the ubiquitination and proteasomal degradation of IκBα. NF-κB then is released to the nucleus and stimulates the expression of proinflammatory genes (7).MAVS-deficient mice show abolished virus-triggered induction of IFNs and increased susceptibility to viral infection (8), indicating that MAVS is essential for the innate immune response. MAVS consists of an N-terminal caspase activation and recruitment domain, a proline-rich domain, and a C-terminal transmembrane domain that targets it to the mitochondrial outer membrane (9). It has been suggested that the mitochondrial outer membrane pr...