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 ␥␦ 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 ␥␦ 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 ␥␦ 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. IMPORTANCEThe 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.

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…In line with this, passive transfer of IFN-γ or perforin-deficient T cells into RAG knockout mice did not confer any noticeable anti-WNV protection [248]. Dysregulation of TLR3 and TLR7 responses in the elderly has also been associated with enhanced vulnerability to lethal WNV infections [249,250].…”

MAVS Is Essential for Primary CD4+T Cell Immunity but Not for Recall T Cell Responses following an Attenuated West Nile Virus Infection

“…Complementary DNA (cDNA) was synthesized using a qScript cDNA synthesis kit (Bio-Rad, Hercules, CA). The sequences of the primer sets for WNV envelope (WNVE), cytokine, and ISG cDNA and PCR conditions were as described previously (11,23,42,43). The assay was performed in the CFX96 real-time PCR system (Bio-Rad).…”

“…cDNA was synthesized by using iScript family reverse transcription kits and then loaded onto 96-well PCR array plates for amplification on the CFX96 real-time PCR system (Bio-Rad). The list of 25 genes was described previously (43). Data analysis was performed by using CFX manager software.…”

TLR8 Couples SOCS-1 and Restrains TLR7-Mediated Antiviral Immunity, Exacerbating West Nile Virus Infection in Mice

“…Defective Tlr7 and type I Ifn genes are contributing factors to not only WNV susceptibility, but to enhanced WNV-induced disease (4, 60, 61). In the current report, we found that TLR8 deficiency in mice induced a strong antiviral immune response, which facilitated efficient control of viral burden and increased survival of mice after lethal WNV challenge.…”