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Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice.

ABSTRACT: Multiple sclerosis (MS) is a complex multifactorial disease of the central nervous system (CNS) for which animal models have mainly addressed downstream immunopathology but not potential inducers of autoimmunity. In the absence of a pathogen known to cause neuroinflammation in MS, Mycobacterial lysate is commonly used in the form of complete Freund's adjuvant to induce autoimmunity to myelin proteins in Experimental Allergic Encephalomyelitis (EAE), an animal model for MS. The present study demonstrates that a protein from the human endogenous retrovirus HERV-W family (MSRV-Env) can be used instead of mycobacterial lysate to induce autoimmunity and EAE in mice injected with MOG, with typical anti-myelin response and CNS lesions normally seen in this model. MSRV-Env was shown to induce proinflammatory response in human macrophage cells through TLR4 activation pathway. The present results demonstrate a similar activation of murine dendritic cells and show the ability of MSRV-Env to trigger EAE in mice. In previous studies, MSRV-Env protein was reproducibly detected in MS brain lesions within microglia and perivascular macrophages. The present results are therefore likely to provide a model for MS, in which the upstream adjuvant triggering neuroinflammation is the one detected in MS active lesions. This model now allows pre-clinical studies with therapeutic agents targeting this endogenous retroviral protein in MS.

SUBMITTER: Perron H

PROVIDER: S-EPMC3855614 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice.

Perron Hervé H Dougier-Reynaud Hei-Lanne HL Lomparski Christina C Popa Iuliana I Firouzi Reza R Bertrand Jean-Baptiste JB Marusic Suzana S Portoukalian Jacques J Jouvin-Marche Evelyne E Villiers Christian L CL Touraine Jean-Louis JL Marche Patrice N PN

PloS one 20131206 12

Multiple sclerosis (MS) is a complex multifactorial disease of the central nervous system (CNS) for which animal models have mainly addressed downstream immunopathology but not potential inducers of autoimmunity. In the absence of a pathogen known to cause neuroinflammation in MS, Mycobacterial lysate is commonly used in the form of complete Freund's adjuvant to induce autoimmunity to myelin proteins in Experimental Allergic Encephalomyelitis (EAE), an animal model for MS. The present study demo ...[more]

PMID: 24324591

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Project description:Discrimination between self vs. non-self and adequate response to infection and tissue damage are fundamental functions of the immune system. The rapid and global spread of known and emerging viruses is a testament that the timely detection of viral pathogens that reproduce within host cells, presents a formidable challenge to the immune system. To gain access to a proper reproductive niche, many pathogens travel via the host vasculature and therefore become exposed to humoral factors of the innate immune system. Although a cascade of coagulation factors plays a fundamental role in host defense for “living fossils” such as horseshoe crabs (Xiphosurida spp), the role of the coagulation system in activation of innate responses to pathogens in higher organisms remains unclear. When human type C adenovirus (HAdv) enters the circulation, 240 copies of coagulation factor X (FX) bind to the virus particle with picomolar affinity. Here, using molecular dynamics flexible fitting (MDFF) and high resolution cryo-electron microscopy (cryo-EM), we defined the interface between the HAdv5 hexon protein and FX at pseudo-atomic level. Based on this structural data, we introduced a single amino acid substitution, T424A, in the hexon that completely abrogated FX interaction with the virus. In vivo genome-wide transcriptional profiling revealed that FX-binding-ablated virus failed to activate a distinct network of the early response genes, whose expression depends on transcription factor NFKB1. Deconvolution of the signaling network responsible for early gene activation showed that the FX-HAdv complex triggers MyD88/TRIF/TRAF6 signaling upon activation of toll-like receptor 4 (TLR4) that serves as a principal sensor of FX-virus complex in vivo. Our study implicates host factor “decoration” of the virus as a mechanism to trigger innate immune sensor that respond to a misplacement of coagulation FX from the blood into intracellular macrophage compartments upon virus entry into the cell. Our results further the mounting evidence of evolutionary conservation between the coagulation system and innate immunity. Two strains of mice, C57BL/6, and Il1r1-/- deficient. Mice were challenged with wild type HAdv5 or HAdv5-based vectors.

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Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice.

Publications

Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice.

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