Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly.
West Nile virus (WNV), a mosquito-borne flavivirus, has recently emerged in North America, and the elderly are particularly susceptible to severe neurological disease and death from infection with this virus. We have investigated the innate immune response of primary human macrophages to WNV in vitro and have found significant differences between the responsiveness of macrophages derived from younger donors and that from older donors. Binding of the glycosylated WNV envelope protein to the C-type lectin dendritic cell-specific intercellular adhesion molecule 3 (ICAM3) grabbing nonintegrin (DC-SIGN) leads to a reduction in the expression of Toll-like receptor 3 (TLR3) in macrophages from young donors via the signal transducer and activator of transcription 1 (STAT1)-mediated pathway. This signaling is impaired in the elderly, and the elevated levels of TLR3 result in an elevation of cytokine levels. This alteration of the innate immune response with aging may contribute to the permeability of the blood-brain barrier and suggests a possible mechanism for the increased severity of WNV infection in older individuals.
Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8031, USA.
Kok-Fai
KF
Kong
Karine
K
Delroux
Xiaomei
X
Wang
Feng
F
Qian
Alvaro
A
Arjona
Stephen E
SE
Malawista
Erol
E
Fikrig
Ruth R
RR
Montgomery
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009656:North America; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000378:metabolism; D014901:West Nile Fever / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D016207:Cytokines; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; D051196:Toll-Like Receptor 3; D014759:Viral Envelope Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C494079:STAT1 protein, human