Impaired Interferon Signaling in Dendritic Cells From Older Donors Infected In Vitro With West Nile Virus

Abstract

West Nile virus (WNV), a mosquito-borne, single-stranded RNA flavivirus, causes significant human morbidity and mortality in the older population; thus, we investigated the effects of aging on infection with WNV in dendritic cells (DCs). We infected DCs with WNV in vitro and quantified cytokines and chemokines (type I IFN and CXCL10), pathogen recognition receptors RIG-I, and Toll-like receptors 3 and 7. The production of type I IFN was significantly lower in DCs from older donors, compared with younger donors. Although we observed no significant age-related difference in expression or nuclear translocation of signaling molecules in initial antiviral responses, DCs from older donors have diminished induction of late-phase responses (eg, STAT1, IRF7, and IRF1), suggesting defective regulation of type I IFN. Our results identify deficits in critical regulatory pathways in the antiviral response that may contribute to the enhanced susceptibility to viral infections observed in aging.

Impaired secretion of interferons by dendritic cells from aged subjects to influenza

“…They produce copious amounts of IFN-I very early in the infection. We (Sridharan et al 2010) and others (Canaday et al 2010;Jing et al 2009;Shodell and Siegal 2002;Stout-Delgado et al 2008;Qian et al 2011) have reported decreased production of IFNs by pDC population in the aged subjects. In addition to pDC, the myeloid dendritic cells (mDCs) subset is also capable of producing IFNs in response to viral infection.…”

“…More recently, Qian et al (2011) have reported decreased IFN-I secretion in monocyte derived DCs from older donors in response to West Nile virus due to decreased induction of STAT-1, IRF-7 and IRF-1. A growing body of evidence demonstrates that chromatin modification is another important mechanism that regulates cytokine expression (Barth and Imhof 2010;Bartova et al 2008;Kouzarides 2007;Strahl and Allis 2000).…”

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

“…Hence, the senescence of the immune system is most likely the main contributor to advanced age as a risk factor for flaviviral infections. A recent study of WNV-infected human dendritic cells showed a weaker immune response to type I interferon (IFN) production in older donors than that in their younger counterparts [133]. Additionally, Piazzi et al determined that changes in memory T-cell phenotype and differentiations were associated with WNV disease severity [129].…”

Quantitative Imaging of Lineage-specific Toll-like Receptor-mediated Signaling in Monocytes and Dendritic Cells from Small Samples of Human Blood

“…We have recently assessed the effects of aging on Toll-like receptors (TLRs), key components of the innate immune system that detect microbial infection and trigger antimicrobial host defense responses . We have shown dysregulation of TLR3 in macrophages and lower production of IFN by DCs from elderly donors in response to infection with West Nile virus 6,7 . Paramount to our understanding of immunosenescence and to therapeutic intervention is a detailed understanding of specific cell types responding and the mechanism(s) of signal transduction.…”

“…In a large cohort of healthy human donors, we showed that peripheral blood monocytes from the elderly have decreased expression and function of certain TLRs 4 and similar reduced TLR levels and signaling responses in dendritic cells (DCs), antigen-presenting cells that are pivotal in the linkage between innate and adaptive immunity 5 . We have shown dysregulation of TLR3 in macrophages and lower production of IFN by DCs from elderly donors in response to infection with West Nile virus 6,7 .…”