Human MARCH1, 2, and 8 block Ebola virus envelope glycoprotein cleavage via targeting furin P domain

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(2)

Published: Feb. 1, 2024

Abstract Membrane‐associated RING‐CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes. Previous work showed that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates MARCH1 and MARCH2 share a similar pattern in restricting EBOV GP‐pseudotyped infection. Human retain GP at the trans ‐Golgi network, reduce its cell surface display, impair virions infectivity. Furthermore, we uncover host proprotein convertase furin could interact with MARCH1/2 intracellularly. Importantly, P domain is verified be recognized by MARCH1/2/8, which critical for their blocking activities. Besides, bovine murine also proteolytic processing. Altogether, our findings confirm of different mammalian origins relatively conserved feature cleavage, provide clues subsequent MARCHs antiviral studies may facilitate development novel strategies antagonize enveloped

Language: Английский

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Milk exosomes elicit a potent anti-viral activity against dengue virus

Journal of Nanobiotechnology, Journal Year: 2022, Volume and Issue: 20(1)

Published: July 6, 2022

Exosomes are nano-sized vesicles secreted by various cells into the intra and extracellular space hence is an integral part of biological fluids including milk. In last few decades, many research groups have proved potential milk exosomes as a sustainable, economical non-immunogenic drug delivery therapeutic agent against different pathological conditions. However, its anti-viral properties still remain to be unearthed.Here, we been able isolate, purify characterize derived from Cow (CME) Goat (GME) further studied antiviral Dengue virus (DENV), Newcastle Disease Virus strain Komarov (NDV-K) Human Immunodeficiency (HIV-1) using in-vitro infection system.TEM, NTA DLS analysis validated appropriate size isolated cow goat (30-150 nm). Real-time PCR immunoblotting results confirmed presence several exosomal miRNAs protein markers. Our findings suggest that GME significantly decreased infectivity DENV. addition, reduces DENV replication reduced secretion mature virions. Furthermore, heat inactivation did not show any inhibition on infection, replication, RNase treatment abrogates indicating direct role in inhibition. addition inhibited NDV-K, but HIV-1, suggesting mediated activity might specific.This study demonstrates opens new avenues for development exosome-based therapies treat viral diseases.

Language: Английский

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HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(15), P. 8001 - 8001

Published: July 27, 2021

Since the discovery of human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in knowledge viral infection, transmission progression HTLV-associated diseases. HTLV-1 is causative agent aggressive adult leukemia/lymphoma inflammatory diseases such as associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cell contribute to defining role HTLV proteins, well mechanisms cell-to-cell virus. Otherwise, selected engineered are currently applied recapitulate vivo pathogenesis verify effectiveness therapy host immune response. Here we review current cell for studying virus-host interaction, restriction factors pathway deregulation mediated by products. We most effective investigate HTLV-1-associated transgenic humanized mice, rabbit monkey models. Finally, summarize studies on STLV BLV, two closely related viruses animals. The recent anticancer HAM/TSP therapies also discussed view reliable experimental that may accelerate translation from findings infected patients.

Language: Английский

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HIV-1 Vpr Functions in Primary CD4+ T Cells

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 420 - 420

Published: March 9, 2024

HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it poised exert various biological effects on the host cell upon delivery. In this way, contributes towards establishment of a successful infection, as evidenced by extent which depends factor achieve full pathogenicity vivo. Although HIV infects types organism, CD4+ T cells are preferentially targeted since they highly permissive productive concomitantly bringing about hallmark immune dysfunction that accompanies spread. The last several decades have seen unprecedented progress unraveling activities possesses at molecular scale, increasingly underscoring importance viral component. Nevertheless, remains controversial whether some these advances bear vivo relevance, commonly employed cellular models significantly differ from primary lymphocytes. One prominent example “established” ability induce G2 cycle arrest, with enigmatic physiological relevance infected objective review discoveries their context illustrate mechanisms whereby supports infection cells, whilst identifying findings require validation physiologically relevant models.

Language: Английский

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Inhibition of IRGM establishes a robust antiviral immune state to restrict pathogenic viruses

EMBO Reports, Journal Year: 2021, Volume and Issue: 22(11)

Published: Sept. 1, 2021

Report1 September 2021Open Access Source DataTransparent process Inhibition of IRGM establishes a robust antiviral immune state to restrict pathogenic viruses Parej Nath Cell Biology and Infectious Diseases Unit, Department Disease Biology, Institute Life Sciences, Bhubaneswar, India School Biotechnology, KIIT University, Search for more papers by this author Nishant Ranjan Chauhan orcid.org/0000-0002-9137-6024 Kautilya Kumar Jena Ankita Datey Molecular Virology Lab, Nilima Dinesh orcid.org/0000-0003-2788-0303 Biomedical Sciences Cells Systems, University Groningen, Medical Center The Netherlands Subhash Mehto Saikat De Tapas Nayak Swatismita Priyadarsini Kshitish Rout Ramyasingh Bal Krushna C Murmu orcid.org/0000-0002-5568-680X Epigenetic Chromatin Manjula Kalia orcid.org/0000-0002-3376-3659 Regional Centre NCR Biotech Science Cluster, Faridabad, Srinivas Patnaik Punit Prasad Fulvio Reggiori orcid.org/0000-0003-2652-2686 Soma Chattopadhyay Corresponding Author [email protected] Santosh orcid.org/0000-0001-9167-5107 Information Nath1,2,†, Chauhan1,†, Jena1,†, Datey3, Kumar4, Mehto1, De3, Nayak3, Priyadarsini1, Rout1, Bal1, Murmu5, Kalia6, Patnaik2, Prasad5, Reggiori4, *,3 *,1 1Cell 2School 3Molecular 4Department 5Epigenetic 6Virology † These authors contributed equally work *Corresponding author. Tel: +91 0674 2304235; E-mail: (lead contact). 2304334; EMBO Reports (2021)22:e52948https://doi.org/10.15252/embr.202152948 PDFDownload PDF article text main figures. Peer ReviewDownload summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract type I interferon (IFN) response is major host arsenal against invading viruses. negative regulator IFN under basal conditions. However, role human during viral infection has remained unclear. In study, we show that expression increased upon infection. induced PAMPs are negatively regulated IRGM. Conversely, depletion results in induction key restriction factors IFITMs, APOBECs, SAMHD1, tetherin, viperin, HERC5/6. Additionally, processes such as MHC-I antigen presentation stress granule signaling enhanced IRGM-deficient cells, indicating cell-intrinsic state. Consistently, IRGM-depleted cells resistant with seven from five different families, Togaviridae, Herpesviridae, Flaviviverdae, Rhabdoviridae, Coronaviridae. Moreover, Irgm1 knockout mice highly chikungunya virus (CHIKV) Altogether, our highlights broad therapeutic target promote defense large number viruses, SARS-CoV-2, CHIKV, Zika virus. Synopsis Depletion Immunity Related GTPase M (IRGM) upregulation several factors. deficient have heightened ability present MHC Class antigens. replication ZIKV SARS-CoV2. Irgm1−/− CHIKV regulates Its triggers anti-viral promotes resistance SARS-CoV2, ZIKV. Introduction Deadly outbreaks significant health concern. A infections treated using drugs, which typically mechanisms (Strasfeld Chou, 2010). most cases, due selective pressure, evolves faster circumvent targeted mechanism become drug addition, vaccine efficacy problem effectively restricting diseases because continuous evolution (Lipsitch, 2019). Due these problems, development host-directed therapies improving immunity could be effective approach, especially emerging strains (Kaufmann et al, 2018). Understanding therefore crucial identify new targets host-based therapies. one components host's innate systems, also operates cell autonomously (Teijaro, 2016). This why multitude developed strategies downregulate response. pattern recognition receptors (PRRs) cGAS, RIG-I, MDA5, TLR9, TLR7, TLR3 sense nucleic acids pathogen-associated molecular patterns (PAMPs) origin induce downstream events leading production IFNs (McNab 2015). interaction cognate activates JAK-STAT1/2 transcriptional hundreds interferon-stimulated genes (ISG's) (Schoggins Rice, 2011; McNab 2015; Teijaro, ISGs effector molecules can inhibit every step propagation, entry, replication, transcription, translation, egression, cell-to-cell transmission Schoggins, addition direct inhibition, immunomodulatory functions Several potent chemokines cytokines trigger infiltration activation clearance infected Thus, identification gene valuable prophylactic, Immunity-related its mouse orthologue regulators inflammation (Bafica 2007; Pei 2017; 2019a, 2019b). We others shown NLRP3 inflammasomes control colon colitis model (Pei 2019a,b). Our recent demonstrated conditions, master regulating cGAS-STING, RIG-I-MAVS, pathways (Jena 2020). it unclear how modulates infections. More importantly, remains established whether inhibiting well-established other depletion. Remarkably, makes them and/or resilient DNA RNA herpes simplex 1 (HSV-1), (ZIKV), West Nile (WNV), vesicular stomatitis (VSV), Japanese encephalitis (JEV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). line findings, were Taken together, blocking an approach protect individuals caused life-threatening Results discussion Viruses First, tested modulated synthetic analogs PAMPs. found three JEV, HSV-I protein (Fig 1A–C). polyinosinic:polycytidylic acid (poly (I:C), analog dsRNA), triple phosphate (5'pppRNA, ligand RIG-I), poly (deoxyadenylic-deoxythymidylic) (dA-dT), B-DNA) significantly at mRNA levels (Figs 1D–F, EV1A B). During infection, cytosolic dsDNA detected cGAS synthesis second messenger cyclic GMP-AMP (cGAMP). cGAMP induces STING pathway, turn increases (Ni both robustly 1G H, EV1C). data PAMP treatment. Figure 1. PAMP-induced suppress A–C. Western blot analysis THP-1 (A) HSV-1 MOI 5 3 h, 6 12 18 24 h (B) (C) JEV h. D–H. untreated or (D) 5'pppRNA (1 μg/ml) (E) Poly I:C 9 (F) dA:dT h,12 (G) (H) probed antibodies indicated. I–L. Control knockdown reporter (I) 8 (J) (K) IFN-β (500 ng/ml) (L) supernatant was subjected luciferase assay QUANTI-Luc reagent (n = 3, mean ± SD, *P < 0.05, **P 0.005, ***P 0.0005, Student's unpaired t-test). M–P. total qRT–PCR primers (M) MX2 (N) ISG15 (O) OAS1 (P) IFN-β. ≤ Q–T. (Q) (R) (S) (T) available online figure. Data [embr202152948-sup-0005-SDataFig1.pdf] Download figure PowerPoint Click here expand EV1. 4 0.005 5'ppp-dsRNA graph depicts efficiency transfection siRNA 4, Viral (I:C) (dA-dT) inducers To test response, first employed (InvivoGen). (I:C)- (dA-dT)-induced substantially 1I J). similar effect observed exposure cGAMP- interferon-β (IFN-β) 1K L). ˜75–80% EV1D). further substantiate finding, performed sentinel responsive genes. IFN-β, MX2, ISG15, strongly 1M–T). suggest PAMPs-induced classical cell-autonomous upregulated cellular proteins establish capable almost all stages life cycle, assembly, egress/release (Goff, 2004; Colomer-Lluch 2018; Urbano Chemudupati 2019; Boso Kozak, 2020) 2A). Each self-sufficient conferring early known their activity SAMD9L, tetherin/BST2, RSAD2/ HERC5/6, OAS's, MX1/2, PKR, TRIM5α Interferon-induced transmembrane (IFITMs) localize membranes entry interrupting membrane fusion between envelope (Weidner 2010; Li 2013; Perreira Compton 2014). SAM domain HD domain-containing (SAMHD1), apolipoprotein B editing enzyme3 (APOBEC3), viperin (RSAD2) nucleotide manipulating enzymes variety NTP's/dNTP's (Sze Gizzi Coggins IFIT's translation initiation binding multisubunit eukaryotic factor (eIF3) interfering assembly preinitiation complex specifically (Fensterl Sen, Human HERC5 HerC6 particle conjugating (ISGylation) various (Durfee Oudshoorn 2012). Tetherin broadly restricts enveloped release tethering budded particles plasma (Neil, 2013). compared transcriptome determine changed absence surprise, (P-value > 1.5 folds) sequencing stable HT-29 epithelial 2B) bone marrow-derived macrophages (BMDMs) 2C). 2. A. Pictorial representation (black font) typical cycle (red IRGM/Irgm1 depleted cells. Created Biorender.com. B, C. Heatmaps representing shRNA (3 biological replicates) irgm1+/+ irgm1−/− BMDMs (2 replicates). D. isolated indicated E. lysates IRGM+/− F. Flag complemented G. transfected S47N H–J. Immunoproteasome TAP leukocyte (HLA) system. K. Antigen uptake representative flow cytometry OVA conjugate AF488 (5 µg/ml, 30 min). fluorescence intensity L, M. processing confocal images DQ-OVA (green) (10 Scale Bar, 10 µm. Graph percentage puncta's N, O. SIINFEKL based H-2Kb-SIINFEKL on surface Irgm1+/+ mg/ml, h). H-2Kb- h) SE, P. Representative (red) h), bar µm (as indicated). Q. granules pathway. R. Immunofluorescence immunostained dsRNA TIA-1 antibody. [embr202152948-sup-0006-SDataFig2.pdf] confirm sequencing, lines. All 2D, EV2A IFNβ serum higher than wild-type EV2C). Next, analyzed factors, IFITM3, APOBEC3G, tetherin. dramatically 2E). Also, ISGylation proteins, hallmark On contrary, overexpression suppressed EV2D). EV2. Key ****P 0.00005, KO each group, OAS1, MX1 IFITM3 overexpressing Mean n t-test. sequential uptake, processing, via II Pathways. si-IRGM Transferrin μg/ml, transferrin transferrin. Scale, μm (upper panel); μm, (lower panel). 25 μm. ensure specificity IRGM-mediated regulation, rescue experiment complementing restored 2F EV2E). essential autophagy anti-inflammatory (Singh 2006; conversion amino residue serine asparagine 47th position (S47N mutation) renders inactive mutant regulate As wild type, catalytic not able efficiently 2G) suggesting required suppression

Language: Английский

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APOBEC3-Related Editing and Non-Editing Determinants of HIV-1 and HTLV-1 Restriction

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1561 - 1561

Published: Feb. 12, 2025

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3/A3) family of cytosine deaminases serves as a key innate immune barrier against invading retroviruses and endogenous retroelements. A3 family's restriction activity these parasites primarily arises from their ability to catalyze cytosine-to-uracil conversions, resulting in genome the accumulation lethal mutations viral genomes. Additionally, non-editing mechanisms, including deaminase-independent pathways, such blocking reverse transcription, have been proposed antiviral strategies employed by proteins. Although factors can influence infection progression, determinants that govern A3-mediated are critical shaping retroviral outcomes. This review examines interactions between retroviruses, specifically human immunodeficiency virus type 1 T-cell leukemia 1, proteins better understand how activities contribute trajectory infections.

Language: Английский

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Intact, recombinant, and spliced forms of endogenous mouse mammary tumor viruses in inbred and wild mice

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

ABSTRACT Endogenous retroviruses (ERVs) are chromosomally integrated viral copies that represent relics of past infections. Analysis the sequenced genomes 17 mouse strains, Mus musculus subspecies, and spretus identified 29 ERVs mammary tumor viruses (MMTVs), termed Mtvs . The 15 laboratory each present in multiple strains reflecting their common breeding history; most predate development inbred were likely acquired by domesticus progenitors but have no orthologs wild mice, whereas four, including intact Mtv1 , endogenized more recently. One 14 found mice was distributed over a broad geographic range southeast Asia. Most full-length, with open reading frames, from many an unusual envelope deletion corresponding to intron rem accessory gene, suggesting its derivation spliced MMTV cDNAs. These deleted envs globally show subspecies-specific sequence variation consistent recurrent generation. highly variable sag responsible for resistance exogenous infection, exhibits evidence recombination as well positive selection, role antiviral defense. In contrast, spread populations is not marked active arms race pitting against cellular receptor. Thus, acquisition potentially disease-inducing recent ongoing process accompanied recombination, deletion. IMPORTANCE inserted into host chromosomes, producing fossil record infections virus-host co-adaptations. ( ) all sister species, strain origins M. although widely shared among none these mice. Among only one showed distribution. All subspecies carry large processed mRNA gene; such derive mRNA. Mtv gene infection under purifying selection has been subject receptor genetic conflicts.

Language: Английский

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Dodging the Host Interferon-Stimulated Gene Mediated Innate Immunity by HIV-1: A Brief Update on Intrinsic Mechanisms and Counter-Mechanisms

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: July 29, 2021

Host restriction factors affect different phases of a viral life cycle, contributing to innate immunity as the first line defense against viruses, including HIV-1. These are constitutively expressed, but triggered upon infection by interferons. Both pre-integration and post-integration events HIV-1 cycle appear play distinct roles in induction interferon-stimulated genes (ISGs), many which encode antiviral factors. However, counteracts mechanisms mediated these through its encoded components. Here, we review recent findings pathways that lead ISGs, employed such IFITMs, APOBEC3s, MX2, ISG15 preventing replication. We also reflect on current understanding counter-mechanisms evade immune responses overcome host Overall, this mini-review provides insights into HIV-1-host cross talk bridging between intracellular research avenues field therapeutic interventions

Language: Английский

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Exploring the presence of bovine leukemia virus among breast cancer tumors in a rural state

Breast Cancer Research and Treatment, Journal Year: 2023, Volume and Issue: 202(2), P. 325 - 334

Published: July 30, 2023

Language: Английский

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Patterns of Evolution of TRIM Genes Highlight the Evolutionary Plasticity of Antiviral Effectors in Mammals

Genome Biology and Evolution, Journal Year: 2023, Volume and Issue: 15(12)

Published: Nov. 21, 2023

The innate immune system of mammals is formed by a complex web interacting proteins, which together constitute the first barrier entry for infectious pathogens. Genes from E3-ubiquitin ligase tripartite motif (TRIM) family have been shown to play an important role in restricting activity different retrovirus species. For example, TRIM5 and TRIM22 both associated with HIV restriction are regarded as crucial parts antiretroviral machinery mammals. Our analyses positive selection corroborate great significance these genes some groups However, we also show that many species lack altogether. By analyzing large number mammalian genomes, here provide comprehensive view evolution eutherians, showcasing pattern accumulation TRIM has dissimilar across orders. data suggest differences caused evolutionary plasticity adapted use strategies combat infections. Altogether, our results insights into representative factors, highlighting example adaptive idiosyncratic system.

Language: Английский

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