title: Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice.
abstract: The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), a mosquito-borne flavivirus, has induced severe neurological symptoms, mostly in the elderly population. No vaccines are available for human use. Recent work showed that an attenuated WNV, a nonstructural (NS) 4B-P38G mutant, induced no lethality but strong immune responses in young (6- to 10-week-old) mice. While studying protective efficacy, we found unexpectedly that old (21- to 22-month) mice were susceptible to WNV NS4B-P38G mutant infection but were protected from subsequent lethal wild-type WNV challenge. Compared to responses in young mice, the NS4B-P38G mutant triggered higher inflammatory cytokine and interleukin-10 (IL-10) production, a delayed γδ T cell expansion, and lower antibody and WNV-specific T cell responses in old mice. Toll-like receptor 7 (TLR7) is expressed on multiple types of cells. Impaired TLR7 signaling in old mice led to dendritic cell (DC) antigen-presenting function compromise and a reduced γδ T cell and regulatory T cell (Treg) expansion during NS4B-P38G mutant infection. R848, a TLR7 agonist, decreased host vulnerability in NS4B-P38G-infected old mice by enhancing γδ T cell and Treg expansion and the antigen-presenting capacity of DCs, thereby promoting T cell responses. In summary, our results suggest that dysregulation of TLR7 partially contributes to impaired innate and adaptive T cell responses and an enhanced vulnerability in old mice during WNV NS4B-P38G mutant infection. R848 increases the safety and efficacy during immunization of old mice with the WNV NS4B-P38G mutant.
  
  
  OBJECTIVE
  The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), an emerging mosquito-borne flavivirus, has induced severe neurological symptoms more frequently in the elderly population. No vaccines are available for human use. Here, we used an aged mouse model to investigate the protective efficacy of an attenuated WNV, the nonstructural 4B-P38G mutant, which was previously shown to induce no lethality but strong immune responses in young adult mice. Studies that contribute to a mechanistic understanding of immune defects in the elderly will allow the development of strategies to improve responses to infectious diseases and to increase vaccine efficacy and safety in aging individuals.
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Guorui
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Huanle
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Pang
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Bi-Hung
authors.initials: BH
authors.lastname: Peng
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Evandro
authors.initials: E
authors.lastname: Winkelmann
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Brenna
authors.initials: B
authors.lastname: McGruder
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hesse
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Campbell
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Gregg N
authors.initials: GN
authors.lastname: Milligan
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Barrett
authors.affiliation: Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA ti1wang@utmb.edu.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
mesh_terms: D056704:Adaptive Immunity; D000367:Age Factors; D000818:Animals; D060467:Disease Resistance; D006651:Histocytochemistry; D007113:Immunity, Innate; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D019562:Viral Load; D014901:West Nile Fever / Q000276:immunology* / Q000473:pathology; D014902:West Nile virus / Q000276:immunology*
chemical_list: D051199:Toll-Like Receptor 7