scholarly journals Type I Interferon Production during Herpes Simplex Virus Infection Is Controlled by Cell-Type-Specific Viral Recognition through Toll-Like Receptor 9, the Mitochondrial Antiviral Signaling Protein Pathway, and Novel Recognition Systems

2007 ◽  
Vol 81 (24) ◽  
pp. 13315-13324 ◽  
Author(s):  
Simon B. Rasmussen ◽  
Louise N. Sørensen ◽  
Lene Malmgaard ◽  
Nina Ank ◽  
Joel D. Baines ◽  
...  
Keyword(s):  
Viral Entry ◽  
Type I Interferon ◽  
Type I ◽  
Toll Like Receptor ◽  
Cell Type ◽  
Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Simplex Virus ◽  
Mitochondrial Antiviral Signaling Protein

ABSTRACT Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes simplex virus (HSV) infection. We show that early production of IFN in vivo is mediated through Toll-like receptor 9 (TLR9) and plasmacytoid dendritic cells, whereas the subsequent alpha/beta IFN (IFN-α/β) response is derived from several cell types and induced independently of TLR9. In conventional DCs, the IFN response occurred independently of viral replication but was dependent on viral entry. Moreover, using a HSV-1 UL15 mutant, which fails to package viral DNA into the virion, we found that entry-dependent IFN induction also required the presence of viral genomic DNA. In macrophages and fibroblasts, where the virus was able to replicate, HSV-induced IFN-α/β production was dependent on both viral entry and replication, and ablated in cells unable to signal through the mitochondrial antiviral signaling protein pathway. Thus, during an HSV infection in vivo, multiple mechanisms of pathogen recognition are active, which operate in cell-type- and time-dependent manners to trigger expression of type I IFN and coordinate the antiviral response.

scholarly journals Cancer Vaccine Immunotherapy with RNA-Loaded Liposomes

2018 ◽  
Vol 19 (10) ◽  
pp. 2890 ◽  
Author(s):  
Elias Sayour ◽  
Hector Mendez-Gomez ◽  
Duane Mitchell
Keyword(s):  
Immune Suppression ◽  
Cancer Vaccines ◽  
Type I Interferon ◽  
Type I ◽  
Toll Like Receptor ◽  
Adaptive Responses ◽  
Receptor Stimulation ◽  
Delivery Vehicles ◽  
Therapeutic Settings

Cancer vaccines may be harnessed to incite immunity against poorly immunogenic tumors, however they have failed in therapeutic settings. Poor antigenicity coupled with systemic and intratumoral immune suppression have been significant drawbacks. RNA encoding for tumor associated or specific epitopes can serve as a more immunogenic and expeditious trigger of anti-tumor immunity. RNA stimulates innate immunity through toll like receptor stimulation producing type I interferon, and it mediates potent adaptive responses. Since RNA is inherently unstable, delivery systems have been developed to protect and deliver it to intended targets in vivo. In this review, we discuss liposomes as RNA delivery vehicles and their role as cancer vaccines.

scholarly journals Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)

2019 ◽  
Vol 221 (Supplement_4) ◽  
pp. S401-S406 ◽  
Author(s):  
Mathieu Iampietro ◽  
Noemie Aurine ◽  
Kevin P Dhondt ◽  
Claire Dumont ◽  
Rodolphe Pelissier ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Critical Role ◽  
Nipah Virus ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Type I ◽  
Antiviral Signaling ◽  
Signaling Protein ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Abstract Interferon (IFN) type I plays a critical role in the protection of mice from lethal Nipah virus (NiV) infection, but mechanisms responsible for IFN-I induction remain unknown. In the current study, we demonstrated the critical role of the mitochondrial antiviral signaling protein signaling pathway in IFN-I production and NiV replication in murine embryonic fibroblasts in vitro, and the redundant but essential roles of both mitochondrial antiviral signaling protein and myeloid differentiation primary response 88 adaptors, but not toll/interleukin-1 receptor/resistance [TIR] domain–containing adaptor–inducing IFN-β (TRIF), in the control of NiV infection in mice. These results reveal potential novel targets for antiviral intervention and help in understanding NiV immunopathogenesis.

scholarly journals DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70

2017 ◽  
Vol 10 (1) ◽  
pp. 44-55 ◽  
Author(s):  
Ken Takashima ◽  
Hiroyuki Oshiumi ◽  
Misako Matsumoto ◽  
Tsukasa Seya
Keyword(s):  
Protein Function ◽  
Adaptor Protein ◽  
Type I ◽  
Promoter Activation ◽  
Antiviral Signaling ◽  
Signaling Protein ◽  
Antiviral Responses ◽  
Complex Functions ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Melanoma differentiation-associated gene 5 (MDA5) is a pattern recognition receptor that recognizes cytoplasmic viral double-stranded RNA (dsRNA) and initiates rapid innate antiviral responses. MDA5 forms a filament-like multimer along the dsRNA leading to oligomerization, which in turn activates the adaptor protein mitochondrial antiviral signaling protein (MAVS) to provide a signal platform for the induction of type I interferon (IFN) and proinflammatory cytokines. The conformational switch of MDA5 causes antiviral defense, but excessive activation of the MDA5-MAVS pathway may result in autoimmune diseases. The regulatory mechanisms of MDA5 activation remain largely unknown. By yeast 2-hybrid, we identified DNAJB1, a member of the HSP40 (heat shock protein 40) family, as an MDA5-binding protein. HSP40s usually cowork with HSP70s. We found that dsRNA stimulation with physiological conditions upregulated the expression levels of DNAJB1 and HSP70; then the proteins were coupled and translocated into the stress granules, where MDA5 encounters dsRNA. DNAJB1 disrupted MDA5 multimer formation, resulting in the suppression of type I IFN induction. The disruption of endogenous DNAJB1 increased MDA5- and MAVS-mediated IFN promoter activation and rendered cells virus resistant. HSP70 inhibitor also enhanced the IFN-inducing function of MDA5 and MAVS. These results suggest that the DNAJB1-HSP70 complex functions for the natural maintenance of RNA sensing by interacting with MDA5/MAVS.

scholarly journals Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback

2020 ◽  
Author(s):  
Aaron B. Lopacinski ◽  
Andrew J. Sweatt ◽  
Christian M. Smolko ◽  
Elise Gray-Gaillard ◽  
Cheryl A. Borgman ◽  
...  
Keyword(s):  
Rna Virus ◽  
Coxsackievirus B3 ◽  
Interferon Response ◽  
Type I ◽  
Viral Pathogens ◽  
Antiviral Signaling ◽  
Viral Binding ◽  
Mitochondrial Antiviral Signaling ◽  
Kinetics Of ◽  
Mitochondrial Antiviral Signaling Protein

SUMMARYComplete kinetic models are pervasive in chemistry but lacking in biological systems. We encoded the complete kinetics of infection for coxsackievirus B3 (CVB3), a compact and fastacting RNA virus. The kinetics are built from detailed modules for viral binding–delivery, translation–replication, and encapsidation. Specific module activities are dampened by the type I interferon response to viral double-stranded RNAs (dsRNAs), which is itself disrupted by viral proteinases. The validated kinetics uncovered that cleavability of the dsRNA transducer mitochondrial antiviral signaling protein (MAVS) becomes a stronger determinant of viral outcomes when cells receive supplemental interferon after infection. Cleavability is naturally altered in humans by a common MAVS polymorphism, which removes a proteinase-targeted site but paradoxically elevates CVB3 infectivity. These observations are reconciled with a simple nonlinear model of MAVS regulation. Modeling complete kinetics is an attainable goal for small, rapidly infecting viruses and perhaps viral pathogens more broadly.

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