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TRL9 pathway activation in response to DNA. TLR9 recognizes ssDNA enriched with CpG and 5′-xCx DNA motifs and changes the conformation of the TLR9 dimers. Dimers come into closer proximity and bind to the Myd88 adaptor. The adaptor recruits IRAK kinases and forms (i) myddosomes composed of MyD88, IRAK4, IRAK1, and IRAK2 that promote the sequential recruitment of TRAF6, TAK1, and MAPKs, leading to the activation of the transcription factors NF-κB, AP-1, and CREB for the production of inflammatory cytokines or alternatively (ii) myddosomes composed of MyD88, IRAK4, and IRAK1 promote the sequential recruitment of TRAF6 and TRAF3, leading to the activation of IRF7 and the production of IFN. Created with BioRender.com.
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DNA virus infections are often lifelong and can cause serious diseases in their hosts. Their recognition by the sensors of the innate immune system represents the front line of host defence. Understanding the molecular mechanisms of innate immunity responses is an important prerequisite for the design of effective antivirotics. This review focuses...
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... Persistent expression of HIV-1 proteins. Several mechanisms can lead to noncanonical translation and the generation of aberrant or cryptic epitopes that potentially HIV DNA and RNA have been demonstrated to trigger inflammatory responses through multiple intracellular PRRs [120][121][122][123]. HIV-1 RT products are associated with the activation of the pathways of the DNA sensors cGAS and IFI16, which activate STING, leading to the induction of interferon-stimulated genes (ISGs), inflammatory cytokines, and the proptosis of CD4+ T cells and myeloid cells [123][124][125][126][127]. Unspliced or intron-containing HIV-1 transcripts stimulate innate immune sensing in myeloid cells through a MAVS-dependent pathway following nuclear export through a CRM1-dependent pathway [94,111,[128][129][130]. RIG-1 detects HIV-1 genomic RNA early in infection [112,[131][132][133] and TLR-3, -7, and -8 sense HIV-1 ssRNAs [114,134,135] to initiate signaling cascades that culminate in the induction of interferon type 1 responses and inflammatory cytokines. ...
People with HIV exhibit persistent inflammation that correlates with HIV-associated comorbidities including accelerated aging, increased risk of cardiovascular disease, and neuroinflammation. Mechanisms that perpetuate chronic inflammation in people with HIV undergoing antiretroviral treatments are poorly understood. One hypothesis is that the persistent low-level expression of HIV proviruses, including RNAs generated from defective proviral genomes, drives the immune dysfunction that is responsible for chronic HIV pathogenesis. We explore factors during HIV infection that contribute to the generation of a pool of defective proviruses as well as how HIV-1 mRNA and proteins alter immune function in people living with HIV.
... Overexpression analyses confirmed that nef-defective primary HIV-1 IMCs are significantly more susceptible to inhibition by IFI16 compared to otherwise isogenic WT viruses (Fig. 6i). IFI16 has been reported to inhibit viral pathogens including HIV-1 by a variety of mechanisms and has also been proposed to play roles in innate sensing of viral pathogens [63][64][65] . Our finding that the inhibitory activity of IFI16 is not only evaded by an additional NF-κB binding site in the LTR of currently dominating clade C viruses 52 but also counteracted by Nef further supports an important role of this antiviral factor. ...
Innate antiviral factors are essential for effective defense against viral pathogens. However, the identity of major restriction mechanisms remains elusive. Current approaches to discover antiviral factors usually focus on the initial steps of viral replication and are limited to a single round of infection. Here, we engineered libraries of >1500 replication-competent HIV-1 constructs each expressing a single gRNAs to target >500 cellular genes for virus-driven discovery of antiviral factors. Passaging in CD4⁺ T cells robustly enriched HIV-1 encoding sgRNAs against GRN, CIITA, EHMT2, CEACAM3, CC2D1B and RHOA by >50-fold. Using an HIV-1 library lacking the accessory nef gene, we identified IFI16 as a Nef target. Functional analyses in cell lines and primary CD4⁺ T cells support that the HIV-driven CRISPR screen identified restriction factors targeting virus entry, transcription, release and infectivity. Our HIV-guided CRISPR technique enables sensitive discovery of physiologically relevant cellular defense factors throughout the entire viral replication cycle.
... Due to the intrinsic instability of genomes, RNA viruses initiate their full-blown replication once they are inside the hosts, thus requiring an ample supply of nucleic acids and other ingredients to sustain the production of progeny virus (Stern-Ginossar et al., 2019). Similarly, DNA viruses also require a sufficient cellular supply of nucleic acids to serve as their building blocks though DNA viruses tend to have much more intricate manipulating mechanisms to evade the host's defense (Huérfano et al., 2022). Upon infection, the virus hijacks the resources of host cells by either disrupting (Yin and Redovich, 2018) or manipulating the host's metabolism (Syed et al., 2010;Kwon et al., 2023) to help its nucleic acid (DNA/RNA) replication (Ghamar Talepoor and Doroudchi, 2022;Mayer et al., 2019). ...
... In addition, the HIV genome also encodes regulatory proteins transactivator of transcription (Tat) and Rev as well as accessory proteins Nef, Vif, Vpu and Vpr. The core is covered by an envelope embedded with glycoprotein gp120 and transmembrane protein gp41, both of which are encoded by the env gene (Huerfano et al., 2022). HIV-1 was first discovered in the summer of, 1983 (Worobey et al., 2016), which can make patients suffer from acquired immunodeficiency syndromes (AIDS) after infecting human body (Deeks et al., 2015). ...
The inflammasome is a multiprotein complex that further regulates cell pyroptosis and inflammation by activating caspase-1. The assembly and activation of inflammasome are associated with a variety of diseases. Accumulative studies have shown that inflammasome is a key modulator of the host’s defense response to viral infection. Indeed, it has been established that activation of inflammasome occurs during viral infection. At the same time, the host has evolved a variety of corresponding mechanisms to inhibit unnecessary inflammasome activation. Therefore, here, we review and summarize the latest research progress on the interaction between inflammosomes and viruses, highlight the assembly and activation of inflammosome in related cells after viral infection, as well as the corresponding molecular regulatory mechanisms, and elucidate the effects of this activation on virus immune escape and host innate and adaptive immune defenses. Finally, we also discuss the potential therapeutic strategies to prevent and/or ameliorate viral infection-related diseases via targeting inflammasomes and its products.
... This leads to innate immune responses eventually recruiting other immune cells to the site of infection and further triggers adaptive immune responses. 131 In 2019, two groups independently reported that the antibody response to AAV is mediated by toll-like receptor 9 (TLR9). They showed that TLR9 was responsible for activating T-cells against an AAV epitope and TLR9 also induces a cytotoxic T-cell response against the transgene resulting in loss of expression. ...
Owing to their small size and safety profiles, adeno-associated viruses (AAVs) have become the vector of choice for gene therapy applications in the retina. In addition to the naturally occurring AAVs, several engineered variants with enhanced properties are being developed for experimental and therapeutic applications. Nonetheless, there are still some challenges impeding successful application of AAVs for a broader range of retinal gene therapies. The small size of AAV particles ensures efficient tissue transduction but also limits the packaging capacity to a few kilobases. Further, AAV’s ability to cross retinal barriers is still an obstacle to pan-retinal transduction of the outer retina with tolerable doses. Lastly, despite overall safety, there have been recent reports of immune responses to AAVs in the eye. Hence, evaluation and prediction of immune responses to AAVs has come to be considered an integral part of future clinical success. This review focuses on the use of AAV in clinical trials for retinal diseases, and discusses developments of variants and novel strategies to overcome immune responses to AAVs.
... One possibility is that Zbp1 regulates the DNA damage response pathway, which is known to be involved in the induction of senescence. Zbp1 has been shown to interact with several DNA repair proteins, including DNA-PK and Ku70, which suggests that it may play a role in regulating DNA repair processes (Yang et al. 2021;Ferguson et al. 2012;Huérfano et al. 2022). Another possibility is that Zbp1 may regulate mitochondrial function, as it has been shown to interact with mitochondrial proteins and localize to mitochondria under certain conditions. ...
The Zbp1 gene has recently emerged as a potential therapeutic target for age-related diseases. Multiple studies have reported that Zbp1 plays a key role in regulating several aging hallmarks, including cellular senescence, chronic inflammation, DNA damage response, and mitochondrial dysfunction. Regarding cellular senescence, Zbp1 appears to regulate the onset and progression of senescence by controlling the expression of key markers such as p16INK4a and p21CIP1/WAF1. Similarly, evidence suggests that Zbp1 plays a role in regulating inflammation by promoting the production of pro-inflammatory cytokines, such as IL-6 and IL-1β, through activation of the NLRP3 inflammasome. Furthermore, Zbp1 seems to be involved in the DNA damage response, coordinating the cellular response to DNA damage by regulating the expression of genes such as p53 and ATM. Additionally, Zbp1 appears to regulate mitochondrial function, which is crucial for energy production and cellular homeostasis. Given the involvement of Zbp1 in multiple aging hallmarks, targeting this gene represents a potential strategy to prevent or treat age-related diseases. For example, inhibiting Zbp1 activity could be a promising approach to reduce cellular senescence and chronic inflammation, two critical hallmarks of aging associated with various age-related diseases. Similarly, modulating Zbp1 expression or activity could also improve DNA damage response and mitochondrial function, thus delaying or preventing the development of age-related diseases. Overall, the Zbp1 gene appears to be a promising therapeutic target for age-related diseases. In the current review, we have discussed the molecular mechanisms underlying the involvement of Zbp1 in aging hallmarks and proposed to develop effective strategies to target this gene for therapeutic purposes.
... Recently, cGAS and IFI16 were shown to be also present in the cell nucleus, where they are suggested to sense infections with DNA viruses (e.g., herpes simplex virus type 1) [16][17][18]. The engagement of the above mentioned PRRs with PAMPs and DAMPs leads to the intracellular activation of signaling pathways that trigger the nuclear translocation of transcription factors, such as nuclear factor kappa B (NFκB) and interferon regulatory factors (IRF) 3 and 7. Upon binding to promoter regions of the host cell DNA, these factors induce the production of pro-inflammatory cytokines, chemokines and type-I interferons (IFN-α and -β) that enter a complex cooperation to control infection [7,14,19]. ...
... It is noteworthy in this regard that in contrast to the situation encountered in hPBMCs, parvovirus replication is required for PRR activation in MEFs. A most likely alternative PRR candidate would thus consist in a DNA sensor linked to the adaptor protein STING, as already suggested by previous investigations using MVMp [62] or FPV [64], such as cGAS, IFI16, DDX41 or DNA-PK [19]. Since cGAS and IFI16 can both be present in the nucleus [18,74], these DNA sensors may indeed detect parvoviruses through their nuclear replication process and represent therefore the most likely candidates. ...
The oncolytic rodent protoparvoviruses (PVs) minute virus of mice (MVMp) and H-1 parvovirus (H-1PV) are promising cancer viro-immunotherapy candidates capable of both exhibiting direct oncolytic activities and inducing anticancer immune responses (AIRs). Type-I interferon (IFN) production is instrumental for the activation of an efficient AIR. The present study aims at characterizing the molecular mechanisms underlying PV modulation of IFN induction in host cells. MVMp and H-1PV triggered IFN production in semi-permissive normal mouse embryonic fibroblasts (MEFs) and human peripheral blood mononuclear cells (PBMCs), but not in permissive transformed/tumor cells. IFN production triggered by MVMp in primary MEFs required PV replication and was independent of the pattern recognition receptors (PRRs) Toll-like (TLR) and RIG-like (RLR) receptors. PV infection of (semi-)permissive cells, whether transformed or not, led to nuclear translocation of the transcription factors NFĸB and IRF3, hallmarks of PRR signaling activation. Further evidence showed that PV replication in (semi-)permissive cells resulted in nuclear accumulation of dsRNAs capable of activating mitochondrial antiviral signaling (MAVS)-dependent cytosolic RLR signaling upon transfection into naïve cells. This PRR signaling was aborted in PV-infected neoplastic cells, in which no IFN production was detected. Furthermore, MEF immortalization was sufficient to strongly reduce PV-induced IFN production. Pre-infection of transformed/tumor but not of normal cells with MVMp or H-1PV prevented IFN production by classical RLR ligands. Altogether, our data indicate that natural rodent PVs regulate the antiviral innate immune machinery in infected host cells through a complex mechanism. In particular, while rodent PV replication in (semi-)permissive cells engages a TLR-/RLR-independent PRR pathway, in transformed/tumor cells this process is arrested prior to IFN production. This virus-triggered evasion mechanism involves a viral factor(s), which exert(s) an inhibitory action on IFN production, particularly in transformed/tumor cells. These findings pave the way for the development of second-generation PVs that are defective in this evasion mechanism and therefore endowed with increased immunostimulatory potential through their ability to induce IFN production in infected tumor cells.
... Beyond the above-mentioned TLRs, NLRs, and RLRs, other sensors could also recognize viral components and elicit immune responses. The cytosolic DNA-sensing pathway known as the cGAS-stimulator of interferon genes (cGAS-STING) signaling can be activated upon cGAS (Cyclic GMP-AMP synthase) recognition of DNA fragments in the cytoplasm, which further activates the enzymatic activity of cGAS to synthesize 2 3 -cGAMP (cyclic guanosine monophosphate-adenosine monophosphate) using ATP and GTP, and cGAMP subsequently activates STING [78][79][80]. Finally, STING recruits and activates the kinases TBK1 and IKKβ resulting in the activation of IRF3 and NF-κB, leading to the activation of IFNs, ISGs, and proinflammatory cytokines, which in turn counteract viral replication [81]. Though cGAS mainly recognizes DNA, accumulating evidence indicates that cGAS-STING activation can also be activated by RNA viruses and in turn inhibit virus replication [82]. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic that has caused disastrous effects on the society and human health globally. SARS-CoV-2 is a sarbecovirus in the Coronaviridae family with a positive-sense single-stranded RNA genome. It mainly replicates in the cytoplasm and viral components including RNAs and proteins can be sensed by pattern recognition receptors including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and NOD-like receptors (NLRs) that regulate the host innate and adaptive immune responses. On the other hand, the SARS-CoV-2 genome encodes multiple proteins that can antagonize the host immune response to facilitate viral replication. In this review, we discuss the current knowledge on host sensors and viral countermeasures against host innate immune response to provide insights on virus–host interactions and novel approaches to modulate host inflammation and antiviral responses.
... pathway known as cGAS-stimulator of interferon genes (cGAS-STING) signaling has been shown to recognize a broad spectrum of viruses, including DNA viruses, RNA viruses, and retroviruses. [17][18][19] STING (also known as MITA, ERIS, MPYS, or TMEM173), an important adaptor in the cell, mediates multiple signaling pathways and plays an important role in antiviral innate immunity. [20][21][22][23] The activator of STING, 2′3′-cGAMP, is produced by the cGAS, which recognizes DNA fragments in the cytoplasm. ...
Recognizing aberrant cytoplasmic double-stranded DNA (dsDNA) and stimulating innate immunity are essential for the host defense against viruses and tumors. Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that synthesizes the second messenger 2'3'-cGAMP and subsequently activates stimulator of interferon genes (STING)-mediated activation of TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and the production of type I interferons (IFN-I). Both the cGAS-STING-mediated IFN-I antiviral defense and the countermeasures developed by diverse viruses have been extensively studied. However, recent studies have revealed a convergent evolutionary feature of SARS-CoV-2 and HIV viral proteins in terms of the selective regulation of cGAS-STING-mediated nuclear factor kappa-B (NF-κB) signaling without any effect on cGAS-STING-mediated TBK1/IRF3 activation and IFN production. The potential beneficial effect of this cGAS-STING-mediated, NF-κB-dependent anti-viral effect and the possible detrimental effect of type I IFN in the pathogenesis of COVID-19 and HIV infection deserve more attention and future investigation. This article is protected by copyright. All rights reserved.
... The structural basis of STING autoinhibition by its CTT should also be considered in future studies. In addition, the structural basis of how the viral protein hijacks the STING for invasion needs further investigation (82,83). Taken together, much more efforts should be spent to further unravel the working mechanism underlying the cGAS-STING pathway, which is useful for us to develop new therapies to fight infections, autoimmune diseases, and cancers. ...
The cGAS-cGAMP-STING pathway is an important innate immune signaling cascade responsible for the sensing of abnormal cytosolic double-stranded DNA (dsDNA), which is a hallmark of infection or cancers. Recently, tremendous progress has been made in the understanding of the STING activation mechanism from various aspects. In this review, the molecular mechanism of activation of STING protein based on its structural features is briefly discussed. The underlying molecular mechanism of STING activation will enable us to develop novel therapeutics to treat STING-associated diseases and understand how STING has evolved to eliminate infection and maintain immune homeostasis in innate immunity.
