Innate Immune Sensing of Modified Vaccinia Virus Ankara (MVA) Is Mediated by TLR2-TLR6, MDA-5 and the NALP3 Inflammasome

PLoS Pathogens

Mariano Esteban¹  Beatriz Perdiguero¹  Carmen E. Gomez¹  Virginie Petrilli²  Jürg Tschopp²  Shizuo Akira³  Didier Le Roy⁴  Quynh-Giao Steiner-Tardivel⁴  Thierry Calandra⁴  Thierry Roger⁴  Julie Delaloye⁴  Marlies Knaup Reymond⁴  Giuseppe Pantaleo⁵ 

[1] Centro Nacional de Biotecnología, CSIC, Ciudad Universitaria Cantoblanco, Madrid, Spain;Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland;Laboratory of AIDS Immunopathogenesis, Immunology and Allergology Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

关键词: Cytokines;    Macrophages;    Chemokines;    Immune response;    Toll-like receptors;    Inflammasomes;    Vaccinia virus;    Transcription factors;   

DOI  :  10.1371/journal.ppat.1000480

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Modified vaccinia virus Ankara (MVA) is an attenuated double-stranded DNA poxvirus currently developed as a vaccine vector against HIV/AIDS. Profiling of the innate immune responses induced by MVA is essential for the design of vaccine vectors and for anticipating potential adverse interactions between naturally acquired and vaccine-induced immune responses. Here we report on innate immune sensing of MVA and cytokine responses in human THP-1 cells, primary human macrophages and mouse bone marrow-derived macrophages (BMDMs). The innate immune responses elicited by MVA in human macrophages were characterized by a robust chemokine production and a fairly weak pro-inflammatory cytokine response. Analyses of the cytokine production profile of macrophages isolated from knockout mice deficient in Toll-like receptors (TLRs) or in the adapter molecules MyD88 and TRIF revealed a critical role for TLR2, TLR6 and MyD88 in the production of IFNβ-independent chemokines. MVA induced a marked up-regulation of the expression of RIG-I like receptors (RLR) and the IPS-1 adapter (also known as Cardif, MAVS or VISA). Reduced expression of RIG-I, MDA-5 and IPS-1 by shRNAs indicated that sensing of MVA by RLR and production of IFNβ and IFNβ-dependent chemokines was controlled by the MDA-5 and IPS-1 pathway in the macrophage. Crosstalk between TLR2-MyD88 and the NALP3 inflammasome was essential for expression and processing of IL-1β. Transcription of the Il1b gene was markedly impaired in TLR2−/− and MyD88−/− BMDM, whereas mature and secreted IL-1β was massively reduced in NALP3−/− BMDMs or in human THP-1 macrophages with reduced expression of NALP3, ASC or caspase-1 by shRNAs. Innate immune sensing of MVA and production of chemokines, IFNβ and IL-1β by macrophages is mediated by the TLR2-TLR6-MyD88, MDA-5-IPS-1 and NALP3 inflammasome pathways. Delineation of the host response induced by MVA is critical for improving our understanding of poxvirus antiviral escape mechanisms and for designing new MVA vaccine vectors with improved immunogenicity.

【 授权许可】

CC BY