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

Guorui Xie, Huanle Luo, Lan Pang, Bihung Peng, Evandro Winkelmann, Brenna McGruder, Joseph Hesse, Melissa Whiteman, Gerald Campbell, Gregg Milligan, Yingzi Cong, Alan Barrett, Tian Wang

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 WNVspecific 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.

Original languageEnglish (US)
Pages (from-to)1333-1344
Number of pages12
JournalJournal of Virology
Volume90
Issue number3
DOIs
StatePublished - 2016

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Toll-Like Receptor 7
West Nile virus
Virus Diseases
T-lymphocytes
T-Lymphocytes
mice
infection
mutants
resiquimod
Infection
antigens
Antigens
Flavivirus
Toll-like receptor 7
Regulatory T-Lymphocytes
dendritic cells
interleukin-10
Culicidae
Interleukin-10
Dendritic Cells

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

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. / Xie, Guorui; Luo, Huanle; Pang, Lan; Peng, Bihung; Winkelmann, Evandro; McGruder, Brenna; Hesse, Joseph; Whiteman, Melissa; Campbell, Gerald; Milligan, Gregg; Cong, Yingzi; Barrett, Alan; Wang, Tian.

In: Journal of Virology, Vol. 90, No. 3, 2016, p. 1333-1344.

Research output: Contribution to journalArticle

Xie, Guorui ; Luo, Huanle ; Pang, Lan ; Peng, Bihung ; Winkelmann, Evandro ; McGruder, Brenna ; Hesse, Joseph ; Whiteman, Melissa ; Campbell, Gerald ; Milligan, Gregg ; Cong, Yingzi ; Barrett, Alan ; Wang, Tian. / 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. In: Journal of Virology. 2016 ; Vol. 90, No. 3. pp. 1333-1344.
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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 WNVspecific 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.",
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AU - Peng, Bihung

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AU - McGruder, Brenna

AU - Hesse, Joseph

AU - Whiteman, Melissa

AU - Campbell, Gerald

AU - Milligan, Gregg

AU - Cong, Yingzi

AU - Barrett, Alan

AU - Wang, Tian

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AB - 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 WNVspecific 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.

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