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Science Advances Sep 2023Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode...
Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode microproteins. However, the landscape and functions of microproteins in responsive to virus infection remain uncharacterized. Here, we systematically identified microproteins that are responsive to vesicular stomatitis virus infection. A conserved and endoplasmic reticulum-localized membrane microprotein, MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrion-localized MAVS protein and inhibit MAVS aggregation and type I interferon signaling activation. The importance of MAVI1 was highlighted that viral infection was attenuated and survival rate was increased in knockout mice. A peptide inhibitor targeting the interaction between MAVI1 and MAVS activated the type I interferon signaling to defend viral infection. Our findings uncovered that microproteins play critical roles in regulating antiviral innate immune responses, and targeting microproteins might represent a therapeutic avenue for treating viral infection.
Topics: Animals; Mice; Immunity, Innate; Antiviral Agents; Endoplasmic Reticulum; Mice, Knockout; Mitochondria; Interferon Type I; Micropeptides
PubMed: 37656786
DOI: 10.1126/sciadv.adg7053 -
Gut Oct 2023Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion,...
OBJECTIVE
Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction.
DESIGN
Metabolic state, exhaustion and transcriptome of virus-specific CD8 T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52 were determined and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested . Intrahepatic virus-specific CD8 T cells were analysed by scRNA-Seq in a HBV-replicating murine model of acute and chronic infection.
RESULTS
HBV-specific (core, polymerase) and HCV-specific (NS3, NS3, NS5B) CD8 T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase -specific CD8 T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core-specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8 T cells in a murine model of chronic infection.
CONCLUSION
Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Antiviral Agents; Persistent Infection; Hepatitis C, Chronic; Hepatitis B, Chronic; Hepatitis C; Hepatitis Viruses; Hepatitis B virus
PubMed: 37541771
DOI: 10.1136/gutjnl-2022-328734 -
The EMBO Journal Jul 2023Interferons (IFNs) are antiviral cytokines that play a key role in the innate immune response to viral infections. In response to viral stimuli, cells produce and... (Review)
Review
Interferons (IFNs) are antiviral cytokines that play a key role in the innate immune response to viral infections. In response to viral stimuli, cells produce and release interferons, which then act on neighboring cells to induce the transcription of hundreds of genes. Many of these gene products either combat the viral infection directly, e.g., by interfering with viral replication, or help shape the following immune response. Here, we review how viral recognition leads to the production of different types of IFNs and how this production differs in spatial and temporal manners. We then continue to describe how these IFNs play different roles in the ensuing immune response depending on when and where they are produced or act during an infection.
Topics: Humans; Interferons; Interferon Regulatory Factor-3; Antiviral Agents; Immunity, Innate; Cytokines; Virus Diseases
PubMed: 37367474
DOI: 10.15252/embj.2022112907 -
Nature Microbiology Jul 2023Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with...
Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with antiviral acyclovir treatment, most patients still experience various neurological sequelae. Here we characterize HSV-1 infection of human brain organoids by combining single-cell RNA sequencing, electrophysiology and immunostaining. We observed strong perturbations of tissue integrity, neuronal function and cellular transcriptomes. Under acyclovir treatment viral replication was stopped, but did not prevent HSV-1-driven defects such as damage of neuronal processes and neuroepithelium. Unbiased analysis of pathways deregulated upon infection revealed tumour necrosis factor activation as a potential causal factor. Combination of anti-inflammatory drugs such as necrostatin-1 or bardoxolone methyl with antiviral treatment prevented the damages caused by infection, indicating that tuning the inflammatory response in acute infection may improve current therapeutic strategies.
Topics: Humans; Herpesvirus 1, Human; Herpes Simplex; Acyclovir; Antiviral Agents; Encephalitis, Viral; Organoids
PubMed: 37349587
DOI: 10.1038/s41564-023-01405-y -
PLoS Pathogens Oct 2023Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally... (Review)
Review
Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally elicited following viral infection and have been characterized in viral infections such as influenza, rotavirus, cytomegalovirus, HIV, and SARS-CoV-2. It has been widely assumed that these nonneutralizing antibodies do not function in a protective way in vivo and therefore are not desirable targets of antiviral interventions; however, increasing evidence now shows this not to be true. Several virus-specific nonneutralizing antibody responses have been correlated with protection in human studies and also shown to significantly reduce virus replication in animal models. The mechanisms by which many of these antibodies function is only now coming to light. While nonneutralizing antibodies cannot prevent viruses entering their host cell, nonneutralizing antibodies work in the extracellular space to recruit effector proteins or cells that can destroy the antibody-virus complex. Other nonneutralizing antibodies exert their effects inside cells, either by blocking the virus life cycle directly or by recruiting the intracellular Fc receptor TRIM21. In this review, we will discuss the multitude of ways in which nonneutralizing antibodies function against a range of viral infections.
Topics: Animals; Humans; Antibodies, Viral; Virus Diseases; Influenza, Human; Receptors, Fc; Antiviral Agents; Antibodies, Neutralizing; HIV Antibodies
PubMed: 37796829
DOI: 10.1371/journal.ppat.1011670 -
Nature Immunology Aug 2023High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the...
High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the origin and relationship of tDCs to other DC subsets has been unclear. Here we show that tDCs are distinct from other well-characterized DCs and conventional DC precursors (pre-cDCs). We demonstrate that tDCs originate from bone marrow progenitors shared with plasmacytoid DCs (pDCs). In the periphery, tDCs contribute to the pool of ESAM type 2 DCs (DC2s), and these DC2s have pDC-related developmental features. Different from pre-cDCs, tDCs have less turnover, capture antigen, respond to stimuli and activate antigen-specific naïve T cells, all characteristics of differentiated DCs. Different from pDCs, viral sensing by tDCs results in IL-1β secretion and fatal immune pathology in a murine coronavirus model. Our findings suggest that tDCs are a distinct pDC-related subset with a DC2 differentiation potential and unique proinflammatory function during viral infections.
Topics: Animals; Mice; Antiviral Agents; Bone Marrow; Cell Differentiation; Dendritic Cells
PubMed: 37414907
DOI: 10.1038/s41590-023-01545-7 -
Frontiers in Immunology 2023Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are... (Review)
Review
Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are recognized as novel regulators of the innate immune response. The antiviral ability of 25HC (25-Hydroxycholesterol) is uncovered due to its role as a metabolic product of the interferon-stimulated gene CH25H (cholesterol-25-hydroxylase). With the advancement of research, the biological functions of 25HC and its structural functions have been interpreted gradually. Furthermore, the underlying mechanisms of antiviral effect of 25HC are not only limited to interferon regulation. Taken up by the special biosynthetic ways and structure, 25HC contributes to modulate not only the cholesterol metabolism but also autophagy and inflammation by regulating signaling pathways. The outcome of modulation by 25HC seems to be largely dependent on the cell types, viruses and context of cell microenvironments. In this paper, we review the recent proceedings on the regulatory effect of 25HC on interferon-independent signaling pathways related to its antiviral capacity and its putative underlying mechanisms.
Topics: Animals; Antiviral Agents; Virus Replication; Interferons; Hydroxycholesterols; Mammals
PubMed: 37781400
DOI: 10.3389/fimmu.2023.1268104 -
The Journal of Infectious Diseases Feb 2024This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56%... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders).
METHODS
Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27.
RESULTS
At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n = 1) and UL97 F342Y (n = 3). Posttreatment, emergent maribavir resistance mutations were detected in 60 (26%) of those randomized to maribavir, including 49 (48%) of 103 nonresponders and 25 (86%) of the 29 nonresponders where viral DNA initially cleared then rebounded while on maribavir. The most common maribavir resistance mutations were UL97 T409M (n = 34), H411Y (n = 26), and C480F (n = 21), first detected 26 to 130 (median 56) days after starting maribavir.
CONCLUSIONS
Baseline maribavir resistance was rare. Drug resistance to standard cytomegalovirus antivirals did not preclude treatment response to maribavir. Rebound in plasma cytomegalovirus DNA while on maribavir strongly suggests emerging drug resistance.
CLINICAL TRIALS REGISTRATION
NCT02931539.
Topics: Humans; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; DNA; Drug Resistance, Viral; Ganciclovir; Mutation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Transplant Recipients
PubMed: 37506264
DOI: 10.1093/infdis/jiad293 -
Nature Microbiology Nov 2023Antiviral signalling, which can be activated in host cells upon virus infection, restricts virus replication and communicates infection status to neighbouring cells. The...
Antiviral signalling, which can be activated in host cells upon virus infection, restricts virus replication and communicates infection status to neighbouring cells. The antiviral response is heterogeneous, both quantitatively (efficiency of response activation) and qualitatively (transcribed antiviral gene set). To investigate the basis of this heterogeneity, we combined Virus Infection Real-time IMaging (VIRIM), a live-cell single-molecule imaging method, with real-time readouts of the dsRNA sensing pathway to analyse the response of human cells to encephalomyocarditis virus (EMCV) infection. We find that cell-to-cell heterogeneity in viral replication rates early in infection affect the efficiency of antiviral response activation, with lower replication rates leading to more antiviral response activation. Furthermore, we show that qualitatively distinct antiviral responses can be linked to the strength of the antiviral signalling pathway. Our analyses identify variation in early viral replication rates as an important parameter contributing to heterogeneity in antiviral response activation.
Topics: Humans; Virus Replication; Signal Transduction; Encephalomyocarditis virus; Antiviral Agents; Virus Diseases
PubMed: 37814072
DOI: 10.1038/s41564-023-01501-z -
World Journal of Gastroenterology May 2024Viral hepatitis represents a major danger to public health, and is a globally leading cause of death. The five liver-specific viruses: Hepatitis A virus, hepatitis B... (Review)
Review
Viral hepatitis represents a major danger to public health, and is a globally leading cause of death. The five liver-specific viruses: Hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus, each have their own unique epidemiology, structural biology, transmission, endemic patterns, risk of liver complications, and response to antiviral therapies. There remain few options for treatment, in spite of the increasing prevalence of viral-hepatitis-caused liver disease. Furthermore, chronic viral hepatitis is a leading worldwide cause of both liver-related morbidity and mortality, even though effective treatments are available that could reduce or prevent most patients' complications. In 2016, the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by the year 2030, along with a discussion of current gaps and prospects for both regional and global eradication of viral hepatitis. Today, treatment is sufficiently able to prevent the disease from reaching advanced phases. However, future therapies must be extremely safe, and should ideally limit the period of treatment necessary. A better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis. This review aims to summarize the current state of knowledge on each type of viral hepatitis, together with major innovations.
Topics: Humans; Antiviral Agents; Hepatitis, Viral, Human; Hepatitis Viruses; Prevalence; Liver
PubMed: 38764770
DOI: 10.3748/wjg.v30.i18.2402