Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

Journal of Virology, Journal Year: 2017, Volume and Issue: 91(15)

Published: May 11, 2017

All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-κB antagonism. However, effect during animal infection is poorly understood. We determined that a K1L-less (vΔK1L) was less pathogenic than wild-type VACV intranasal and intradermal infection. Decreased pathogenicity correlated with diminished replication intranasally infected mice. intradermally inoculated ears, vΔK1L replicated levels nearly identical those VACV, implying decreased not replication, dictated lesion size. Several lines evidence support this theory. First, induced slightly edema vK1L, as revealed by histopathology noninvasive quantitative ultrasound technology (QUS). Second, infiltrating cell populations were vΔK1L-infected ears. Third, cytokine chemokine gene expression While these results identified biological basis for smaller lesions, they remained puzzling; because antagonizes vitro, expected be higher Despite innate responses, vaccination protective VACV-specific CD8+ T protected against lethal challenge. Thus, first construct reported caused muted profile infiltration an model yet still elicited immunity.IMPORTANCE inhibits activation among its other antagonistic functions. A lacking predicted it would trigger more robust VACV. Indeed, mouse ear pinnae. unexpectedly dramatically reduced cells into This likely due genes As such, our finding contradicted observations from systems. Interestingly, conferred immunity suggests triggered sufficient mount effective response. Our highlight complexity unpredictable nature virus-host interactions, relationship must understood better comprehend pathogenesis or manipulate use vaccines.

Language: Английский

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Poxviral Targeting of Interferon Regulatory Factor Activation

Viruses, Journal Year: 2020, Volume and Issue: 12(10), P. 1191 - 1191

Published: Oct. 20, 2020

As viruses have a capacity to rapidly evolve and continually alter the coding of their protein repertoires, host cells evolved pathways sense through one invariable feature common all these pathogens—their nucleic acids. These genomic transcriptional pathogen-associated molecular patterns (PAMPs) trigger activation germline-encoded anti-viral pattern recognition receptors (PRRs) that can distinguish viral acids from forms by localization subtle differences in chemistry. A wide range transmembrane cytosolic PRRs probe intracellular environment for PAMPs, activating leading gene expression. The Nuclear Factor Kappa B (NFκB) Interferon (IFN) Regulatory (IRF) family transcription factors are central importance driving pro-inflammatory type-I interferon (TI-IFN) expression required effectively restrict spread adaptive responses clearance. Poxviruses complex arrays inhibitors which target at variety levels. This review will focus on how poxviruses inhibit PRR IRF factors.

Language: Английский

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IL-1R Type 1–Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection

The Journal of Immunology, Journal Year: 2017, Volume and Issue: 198(11), P. 4341 - 4351

Published: May 4, 2017

Abstract The IL-1 superfamily of cytokines and receptors has been studied extensively. However, the specific roles elements in host immunity to cutaneous viral infection remain elusive. In this study, we applied vaccinia virus (VACV) by scarification IL-1R1 knockout mice (IL-1R1−/−) found that these developed markedly larger lesions with higher genome copies skin than did wild-type mice. phenotype infected IL-1R1−/− was similar eczema vaccinatum, a severe side effect VACV vaccination may develop humans atopic dermatitis. Interestingly, impaired response not reflect systemic immune deficiency, because immunized survived subsequent lethal intranasal challenge, or defects T cell activation homing site inoculation. Histologic evaluation revealed replication after were limited epidermal layer mice, whereas lack permitted extension into dermal layers skin. We explored etiology discrepancy determined contained significantly more macrophages monocyte-derived dendritic cells dermis scarification. These vulnerable augment transmission adjacent skin, thus leading satellite results suggest new therapeutic strategies for treatment vaccinatum inform assessment risks patients receiving blocking Abs chronic inflammatory disorders.

Language: Английский

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MyD88 is an essential regulator of NK cell-mediated clearance of MCMV infection

Molecular Immunology, Journal Year: 2021, Volume and Issue: 137, P. 94 - 104

Published: July 6, 2021

Language: Английский

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Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2019, Volume and Issue: unknown

Published: April 23, 2019

Abstract Type I interferons (T1-IFN) are critical in the innate immune response, acting upon infected and uninfected cells to initiate an antiviral state by expressing genes that inhibit multiple stages of lifecycle many viruses. T1-IFN triggers production Interferon-Stimulated Genes (ISGs), activating program reduces virus replication. The importance response is highlighted evolution viral evasion strategies or action virus-infected cells. produced via activation pathogen sensors within cells, a process targeted virus-encoded immunomodulatory molecules. This probably best exemplified prototypic poxvirus, Vaccinia (VACV), which uses at least 6 different mechanisms completely block vitro . Yet, mice lacking aspects signaling often more susceptible infection with viruses, including VACV, than wild-type mice. How can these opposing findings be rationalized? cytosolic DNA sensor cGAS has been implicated immunity but yet linked VACV infection. Indeed, there two VACV-encoded proteins effectively prevent cGAS-mediated T1-IFN. We find majority VACV-infected vivo do not produce T1-IFN, small subset utilize sense protect protective effect mediated ISG-mediated control Rather, drives expression CCL4, recruits inflammatory monocytes constrain lesion replication-independent manner limiting spread tissue. Our have broad implications our understanding detection , highlight novel strategy Summary recognition leads quick robust type (T1-IFN). Nearly all viruses acquired induction order attain replicative advantage. Some thwart so thoroughly, any And yet, animal models defects sensitive their counterparts. In this study, we evidence explain otherwise contradicting findings. show population able pathogen-sensing pathway blocked specialized protects recruiting restrict tissue, independent burden. direct impact on how detected present system limit pathology peripheral sites

Language: Английский

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Role of Lamin A/C on dendritic cell function in antiviral immunity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 17, 2024

Abstract Dendritic cells (DCs) play a crucial role in orchestrating immune responses, particularly promoting IFNγ-producing-CD8 cytotoxic T lymphocytes (CTLs) and IFNγ-producing -CD4 helper 1 (Th1) cells, which are essential for defending against viral infections. Additionally, the nuclear envelope protein lamin A/C has been implicated cell immunity. Nevertheless, intricate interplay between innate adaptive immunity response to infections, of DC functions within this context, remains poorly understood. In study, we demonstrate that mice lacking myeloid LysM promoter-expressing exhibit reduced capacity induce Th1 CD8 CTL leading impaired clearance acute primary Vaccinia virus (VACV) infection. Remarkably, vitro -generated granulocyte macrophage colony-stimulating factor bone marrow-derived DCs (GM-CSF BMDCs) show high levels A/C. Lamin absence on GM-CSF BMDCs does not affect expression costimulatory molecules membrane but it reduces cellular ability form immunological synapses with naïve CD4 cells. deletion induces alterations NFκB localization, thereby influencing NFκB-dependent transcription. Furthermore, ablation modifies epigenetic signature BMDCs, predisposing these mount less effective antiviral upon TLR stimulation. This study highlights critical interacting during responses elucidates molecular mechanisms through modulates function via transcriptional regulation.

Language: Английский

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Role of lamin A/C on dendritic cell function in antiviral immunity

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Sept. 12, 2024

Language: Английский

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Systems vaccinology analysis of a recombinant vaccinia-based vector reveals diverse innate immune signatures at the injection site

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: Aug. 18, 2020

Abstract Poxvirus systems have been extensively used as vaccine vectors. Herein a vaccinology analysis of intramuscular injection sites provides detailed insights into host innate immune responses, well expression vector and recombinant immunogen genes, after vaccination with new multiplication defective, vaccinia-based vector, Sementis Copenhagen Vector. Chikungunya Zika virus mRNA protein was associated necrosing skeletal muscle cells surrounded by mixed cellular infiltrates. Adjuvant signatures at 12 hours post-vaccination were dominated TLR3, 4 9, STING, MAVS, PKR the inflammasome. Th1 cytokine IFNγ, TNF IL1β, chemokine CCL5 CXCL12. Multiple dendritic cell stimulation evident. By day seven, transcripts absent, death, neutrophil, macrophage inflammation annotations had abated. No compelling arthritis identified. Such approaches should inform refinements in poxvirus-based design.

Language: Английский

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γδ T cells mediate a requisite portion of a wound healing response triggered by cutaneous poxvirus infection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: Sept. 1, 2020

Abstract Infection at peripheral sites, such as the skin, activates local innate immune defenses tasked with limiting spread of pathogen while preserving tissue integrity. T cells bearing γδ Cell Receptors (TCR), which comprise multiple phenotypically distinct subtypes cells, reside in normal where they shape immunity to cutaneous infection, prior onset an adaptive response by conventional αβ CD4 + (T CD4+ ) and CD8 CD8+ cells. The mechanisms used control virus replication pathology following infection are unknown, so we examined role vaccinia (VACV). Resident skin expanded combined recruited observed after VACV infection. However, no defect or increased systemic mice lacking despite induction a cytolytic specialized subset resident While examining cell-mediated identified unique wound healing signature associated that has features common to, but also antagonize, sterile response. Typically, repair is thought occur only clearance pathogen, viral was evident peak skin. contributed this through cytokines growth factors required for efficient closure. Therefore, early mediators likely important maintenance barrier function prevention secondary bacterial Author Summary among first cell types positioned be able respond it assumed these play similar their widespread throughout body, namely kill infected slow spread. found Rather, functioned critical component previously unrecognized started occurs same time aims clear virus. This study describe both response, information could allow manipulation decrease change scarring infections.

Language: Английский

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