title: A West Nile virus NS4B-P38G mutant strain induces adaptive immunity via TLR7-MyD88-dependent and independent signaling pathways.
abstract: Prior work shows that an attenuated West Nile virus (WNV), the nonstructural (NS)4B-P38G mutant infection in mice induced strong immune responses and protected host from subsequent lethal wild-type WNV infection. Here, we investigated NS4B-P38G mutant infection in myeloid differentiation factor 88-deficient (MyD88(-/-)) and Toll-like receptor 7-deficient (TLR7(-/-)) mice and found they had enhanced susceptibility compared to wild-type mice. Both groups had lower WNV-specific IgM response and reduced effector T cell functions. Dendritic cells (DCs) also exhibited a reduced maturation and impaired antigen-presenting functions compared to wild-type DCs. Moreover, infection with NS4B-P38G mutant in TLR7(-/-) and MyD88(-/-) mice provided full and partial protection respectively from subsequent challenge with lethal wild-type WNV. There were reduced T cell responses in MyD88(-/-) and interleukin-1 receptor deficient (IL-1R(-/-)) mice during secondary challenge with wild-type WNV. In contrast, TLR7(-/-) mice displayed normal T cell functions. Collectively, these results suggest that TLR7-dependent MyD88 signaling is required for T cell priming during NS4B-P38G mutant infection, whereas the TLR7-independent MyD88 signaling pathways are involved in memory T cell development, which may contribute to host protection during secondary challenge with wild-type WNV.
authors.affiliation: Department of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Guorui
authors.initials: G
authors.lastname: Xie
authors.forename: Thomas
authors.initials: T
authors.lastname: Welte
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Whiteman
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wicker
authors.forename: Vandana
authors.initials: V
authors.lastname: Saxena
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
authors.forename: Alan D T
authors.initials: AD
authors.lastname: Barrett
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
mesh_terms: D056704:Adaptive Immunity; D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions; D056724:Immunity, Humoral; D007156:Immunologic Memory; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014902:West Nile virus / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7
keywords: B6; BM; C57BL/6; CNS; DCs; E; IFN; Immune response; LD; MyD88; NS; NS4B protein; Q-PCR; T cell; TLR; Toll-like receptor; WNV; West Nile virus; bone marrow; central nervous system; dendritic cells; envelope; i.p.; interferon; intraperitoneally; lethal dose; myeloid differentiation factor 88; nonstructural; quantitative PCR