Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 10, 2024

Abstract Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation inflammatory prevents cytokine storm usually occurs HTNV-infected patients. This attained elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, receptors activated HTNV enhance signaling recruiting IKKβ p65, promoting polarization both species. However, mice rather than Notch-mediated inflammation timely restrained a series murine-specific long noncoding RNAs transcribed pathway negative feedback manner. Among them, lnc-ip65 detaches p65 from receptor inhibits phosphorylation, rewiring macrophages pro-inflammation pro-resolution phenotype. Genetic ablation leads destructive mice. Thus, our findings reveal an immune-braking function murine RNAs, offering special therapeutic strategy for infection.

Language: Английский

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UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 26, 2024

Abstract The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for initiation of antiviral immune responses. RLRs subjected to stringent transcriptional and posttranslational regulations, which ubiquitination is one most important. However, role in RLR transcription unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator transcription. UBR5 deficiency reduces responses viruses, while increases replication primary cells mice. Ubr5 mice more susceptible lethal virus infection than wild type littermates. Mechanistically, mediates Lysine 63-linked Tripartite Motif 28 (TRIM28), an epigenetic repressor RLRs. This modification prevents intramolecular SUMOylation TRIM28, thus disengages TRIM28-imposed brake on In sum, enables rapid upregulation expression boost by ubiquitinating de-SUMOylating TRIM28.

Language: Английский

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A Novel pH‐Responsive Baicalein@Chitosan Hydrogel for the Topical Treatment of Herpes Simplex Virus Type 1 Skin Infections: Therapeutic Potential and Mechanisms

Advanced Healthcare Materials, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Abstract Herpes simplex virus type 1 (HSV‐1) is a prevalent human pathogen primarily transmitted through skin‐to‐skin contact. Traditional antiviral drugs like acyclovir (ACV) have limitations due to viral resistance and side effects, necessitating the development of alternative therapeutic strategies. Drug‐loaded hydrogels emerged as promising approach for managing various skin infections. Considering low‐pH microenvironment following HSV‐1 infection, pH‐responsive baicalein@chitosan (B@C) hydrogel developed topical treatment This synthesized by incorporating baicalein, natural flavonoid, into chitosan matrix modified with 4‐formylphenylboronic acid protocatechualdehyde achieve potent anti‐HSV‐1 activity pH‐responsiveness. In vitro results demonstrated hydrogel's pH‐dependent inhibitory effect on infections, including ACV‐resistant strains. Subsequent investigations confirmed its efficacy in multiple murine infection models. Mechanistically, B@C inhibited replication modulating phosphorylation inhibitor nuclear factor kappa‐B kinase subunit beta, promoted collagen synthesis, decreased reactive oxygen species generation. Ultra‐high‐performance liquid chromatography‐tandem mass spectrometry analysis revealed sustained release baicalein from hydrogel, ensuring long‐term drug retention HSV‐1‐infected tissues. Collectively, these findings suggest that holds significant potential management

Language: Английский

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Goose IFIT5 positively regulates goose astrovirus replication in GEF cells

Poultry Science, Journal Year: 2024, Volume and Issue: 103(8), P. 103930 - 103930

Published: June 1, 2024

Interferon-induced protein with tetratricopeptide repeats (IFITs), a family of proteins strongly induced by type I interferon (IFN-I), are deeply involved in many cellular and viral processes. IFIT5, the sole this found birds, also plays crucial role regulating virus infection. In study, goose IFIT5 (gIFIT5) was first cloned from peripheral blood lymphocyte (PBL) phylogenetic analysis showed that it highly homologous duck (dIFIT5), sharing 94.6% identity amino acid sequence. Subsequently, expression kinetics gIFIT5 during astrovirus (GAstV) infection regulatory effect on GAstV proliferation were evaluated. Results mRNA level greatly infection, especially at 12 hpi. Importantly, could conversely promote replication GEF cells. Virus titers overexpression group significantly higher than those control 24 Western blot quantitative real-time PCR (qRT-PCR) further demonstrated production cap facilitated gIFIT5-transfected group. Collectively, facilitates self-replication via promoting expression.

Language: Английский

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Mouse guanylate‐binding protein 1 does not mediate antiviral activity against influenza virus in vitro or in vivo

Immunology and Cell Biology, Journal Year: 2023, Volume and Issue: 101(5), P. 383 - 396

Published: Feb. 6, 2023

Abstract Many interferon (IFN)‐stimulated genes are upregulated within host cells following infection with influenza and other viruses. While the antiviral activity of some IFN‐stimulated genes, such as IFN‐inducible GTPase myxoma resistance (Mx)1 protein 1, has been well defined, less is known regarding activities related GTPases guanylate‐binding (GBP) family, particularly mouse GBPs, where models can be used to assess their properties in vivo . Herein, we demonstrate that GBP1 (mGBP1) was a airway epithelial cell line (LA‐4 cells) pretreatment IFNα or by A virus (IAV). Whereas doxycycline‐inducible expression Mx1 (mMx1) LA‐4 resulted reduced susceptibility IAV viral growth, inducible mGBP1 did not. Moreover, primary isolated from mGBP1‐deficient mice (mGBP1 −/− ) showed no difference macrophages defect IAV‐induced NLRP3 (NLR family pyrin domain containing 3) inflammasome activation. After intranasal infection, also differences replication induction inflammatory responses airways during infection. Thus, using complementary approaches overexpression, does not play major role modulating vitro

Language: Английский

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TRIM16 Overexpression in HEK293T Cells Results in Cell Line-Specific Antiviral Activity

Pathogens, Journal Year: 2023, Volume and Issue: 12(6), P. 852 - 852

Published: June 20, 2023

Host cell restriction factors are intracellular proteins that can inhibit virus replication. Characterisation of novel host provide potential targets for host-directed therapies. In this study, we aimed to assess a member the Tripartite-motif family protein (TRIM) family, TRIM16, as putative factor. To end, utilized constitutive or doxycycline-inducible systems overexpress TRIM16 in HEK293T epithelial cells and then tested its ability growth by range RNA DNA viruses. cells, overexpression resulted potent inhibition multiple viruses, however, when was overexpressed other lines (A549, Hela, Hep2), not observed. When investigating antiviral activity endogenous report siRNA-mediated knockdown A549 also modulated mRNA expression TRIM proteins, complicating interpretation results using method. Therefore, used CRISPR/Cas9 editing knockout demonstrate did mediate against viruses tested. Thus, while initial suggested factor, alternative approaches validate these findings. These studies highlight importance complementary experimental approaches, including analysis investigation protein, defining with activity.

Language: Английский

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Expression of a Functional Mx1 Protein Is Essential for the Ability of RIG-I Agonist Prophylaxis to Provide Potent and Long-Lasting Protection in a Mouse Model of Influenza A Virus Infection

Viruses, Journal Year: 2022, Volume and Issue: 14(7), P. 1547 - 1547

Published: July 15, 2022

RIG-I is an innate sensor of RNA virus infection and its activation induces interferon-stimulated genes (ISGs). In vitro studies using human cells have demonstrated the ability synthetic agonists (3pRNA) to inhibit IAV replication. However, in mouse models effectiveness 3pRNA reported date differs markedly between studies. Myxoma resistance (Mx)1 ISG protein which mediates potent anti-IAV activity, however most inbred strains do not express a functional Mx1. Herein, we utilised C57BL/6 mice that (B6.A2G-Mx1) (B6-WT) Mx1 assess prophylactic treatment induce ISGs protect against subsequent infection. vitro, primary lung from B6-WT B6.A2G-Mx1 resulted induction inhibition was more mice. vivo, single intravenous injection lungs both mice, long-lasting protection challenge only observed Thus, despite broad induction, expression critical for agonist-mediated model

Language: Английский

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Mouse guanylate-binding proteins of the chromosome 3 cluster do not mediate antiviral activity in vitro or in mouse models of infection

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Aug. 25, 2024

Dynamin-like GTPase proteins, including myxoma (Mx) and guanylate-binding proteins (GBPs), are among the many interferon stimulated genes induced following viral infections. While studies report that human (h)GBPs inhibit different viruses in vitro, few have convincingly demonstrated mouse (m)GBPs mediate antiviral activity, although mGBP-deficient mice been used extensively to define their importance immunity diverse intracellular bacteria protozoa. Herein, we demonstrate individual (overexpression) or collective (knockout (KO) mice) mGBPs of chromosome 3 cluster (mGBPchr3) do not replication five from virus families nor observe differences titres recovered wild type versus mGBPchr3 KO after infection with three these (influenza A virus, herpes simplex 1 lymphocytic choriomeningitis virus). These data indicate appear be a major component cell-intrinsic against tested our studies. Mouse guanylate binding potent activity vitro vivo.

Language: Английский

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Regulatory pathway underpinning the development of encephalitis after simian immunodeficiency virus infection in rhesus macaques (Macaca mulatta)

Journal of Medical Primatology, Journal Year: 2023, Volume and Issue: 52(4), P. 259 - 271

Published: June 5, 2023

Abstract Background Simian immunodeficiency virus (SIV) infection in rhesus macaques ( Macaca mulatta ) can lead to the development of SIV encephalitis (SIVE), which is closely related human (HIV)‐induced dementia. Methods This was done by analyzing and SIVE infected M. hippocampus samples from two microarray data sets, identifying groups common differentially expressed genes predicting associated protein interactions. Results We found that eight genes— MX1 , B2M IFIT1 TYMP STAT1 IFI44 ISG15 IFI27 —affected negative regulation biological processes, hepatitis C Epstein–Barr viral infection, toll‐like receptor signaling pathway, mediate after infection. In particular, played a central role process regulating biopathological changes during SIVE. Conclusion These findings provide new theoretical basis for treatment encephalopathy HIV targeting .

Language: Английский

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