Age-related alterations in immune responses to West Nile virus infection

Abstract

SummaryWest Nile virus (WNV) is the most important causative agent of viral encephalitis worldwide and an important public health concern in the United States due to its high prevalence, severe disease, and the absence of effective treatments. Infection with WNV is mainly asymptomatic, but some individuals develop severe, possibly fatal, neurological disease. Individual host factors play a role in susceptibility to WNV infection, including genetic polymorphisms in key anti-viral immune genes, but age is the most well-defined risk factor for susceptibility to severe disease. Ageing is associated with distinct changes in immune cells and a decline in immune function leading to increased susceptibility to infection and reduced responses to vaccination. WNV is detected by pathogen recognition receptors including Toll-like receptors (TLRs), which show reduced expression and function in ageing. Neutrophils, monocyte/macrophages and dendritic cells, which first recognize and respond to infection, show age-related impairment of many functions relevant to antiviral responses. Natural killer cells control many viral infections and show agerelated changes in phenotype and functional responses. A role for the regulatory receptors Mertk and Axl in blood-brain barrier permeability and in facilitating viral uptake through phospholipid binding may be relevant for susceptibility to WNV, and age-related up-regulation of Axl has been noted previously in human dendritic cells. Understanding the specific immune parameters and mechanisms that influence susceptibility to symptomatic WNV may lead to a better understanding of increased susceptibility in elderly individuals and identify potential avenues for therapeutic approaches: an especially relevant goal, as the world's populating is ageing.

West Nile Virus Seroprevalence, Connecticut, USA, 2000–2014

“…Although age is a critical risk factor for severe WNV infection ( 3 , 9 ), the mean age of seropositive and seronegative nonimmunosuppressed participants did not differ significantly (Table). The rate of asymptomatic seroconversion did not vary significantly among the 890 persons in 3 age groups: <35 years (42/421), 35–65 years (7/121), and >65 years (27/348) (p = 0.338).…”

“…However, mean age of symptomatic case-patients was older than that of asymptomatic seropositive participants, indicating that age remains a factor in disease susceptibility ( 9 ). Age has a well-documented role in decreased immune cell function and increased susceptibility to infectious diseases, including WNV ( 9 , 10 ); dysregulation of immune responses with elevated cytokine levels may contribute to development of severe disease. The higher WNV seroprevalence among immunosuppressed adults strongly suggests a key role for immune factors in seroconversion.…”

“…Ongoing research seeks to further define the immune system attributes that lead to increased risk for higher WNV disease severity; active areas of interest include genomic, transcriptional, and immune- and age-related variable responses ( 6 , 8 , 9 ). In addition to environmental conditions that affect vector abundance, our study suggests that individual variation, such as immune status, may be a key driver for susceptibility to infection and disease severity and for differing seroconversion rates among neighbors.…”

Mapping innate and adaptive immune function in arbovirus infections

“…During the febrile phase of Dengue, there is an increase in frequency of CD56 hi CD16 − NKC, the subset considered to function through cytokine release . In West Nile Virus infection, on the other hand, a protective role of NKC has been invoked and enhanced susceptibility comes with ageing . Chan and Ng point out that a key factor generally in evaluation of innate and adaptive immune subsets to arboviral disease outcome is the differential impact of host immune senescence …”

“…9 In West Nile Virus infection, on the other hand, a protective role of NKC has been invoked and enhanced susceptibility comes with ageing. 10 Chan and Ng point out that a key factor generally in evaluation of innate and adaptive immune subsets to arboviral disease outcome is the differential impact of host immune senescence. 11 Analysis of changes to the Treg compartment can be an important step in evaluating the balance between host defence and regulation of collateral damage in achieving a balance between pathogen clearance and immunopathology.…”