West Nile Virus is most deadly among individuals aged 60 and older, though the reasons behind this have been unclear. Now, a new study published in PLOS Pathogens claims to have found an explanation.
Study author Michael Diamond, of Washington University in St. Louis, and colleagues found that many important components of the early immune response to the West Nile Virus (WNV) were impaired in elderly mice, which may explain why elderly people are more vulnerable to the virus.
WNV is most common in Africa, Europe, the Middle East, North America and West Asia. The virus is primarily transmitted to humans through the bite of an infected mosquito.
Around 70-80% of people who become infected with WNV will not experience symptoms, while around 20% of infected people may experience fever, diarrhea, headache, rash, body aches, joint pains and vomiting.
In less than 1% of cases, WNV can cause neurological illness, such as encephalitis or meningitis. Symptoms include headache, fever, disorientation, tremors, coma, muscle weakness and paralysis. Death occurs in around 10% of severe WNV cases.
While serious illness from WNV can occur in individuals of any age, the elderly are most at risk. “In the elderly, the virus crosses the blood-brain barrier at increased frequency and infects neurons of the brain and spinal cord; this is associated with a 5-10% case-fatality rate,” note Diamond and colleagues.
For their study, the team sought to determine the mechanisms underlying elderly individual’s vulnerability to WNV.
The researchers infected 4-month-old mice (the equivalent to young adults) and 18-month-old mice (the equivalent to elderly adults) with WNV.
Compared with younger mice, the older mice were three times more likely to die from WNV infection. What is more, the virus levels in the brains of older mice were 20 times higher than those of the younger mice.
- Birds are the natural host of WNV – mosquitoes become infected by feeding on infected birds
- Though there is a vaccine to protect horses against WNV, there is currently no vaccine to protect humans against the virus
- The majority if WNV infections in the US occur between June and September.
The researchers compared and analyzed the immune response to WNV infection of the older mice with that of the younger mice.
Shortly after transmission of WNV, the early specific immune response, or adaptive immune response, to the virus was weaker in the older mice than in the younger mice. In other words, the WNV-specific antibody responses in the older mice were less potent than those of the younger mice. Older mice also had weaker long-term antibody memory responses than younger mice.
In addition, the researchers found that the formation of “germinal centers” in the older mice was delayed.
Germinal centers are the home to draining lymph nodes (DLNs), which are areas close to the initial infection site. Immune cells – antigen-presenting cells, helper T cells and B cells – flock to DLNs and form the germinal centers in order to create a specific antibody response. A delay in formation of these germinal centers explains the weaker adaptive immune response identified in older mice.
On closer examination of the DLNs in the older mice, the team found there were fewer helper T cells, which indicates that the helper T cells of older mice have a lesser ability to migrate to DLNs.
This theory was confirmed when the researchers transplanted helper T cells from both younger and older mice into younger mice. Using live microscopy, they saw that the helper T cells of older mice were less able to flock to DLNs.
The team also found that the DLNs of the older mice had lower levels of immune stimulators called chemokines, which reduced their ability to attract other immune cells in order to form germinal centers.
The researchers note that, while the identified impairments in the DLNs of older mice were moderate, even short delays in the migration of immune cells to DLNs may trigger a reduction in WNV-specific antibody response in the early stages of infection.
A reduction in the WNV-specific antibody response after transmission can lead to higher viral loads early on, the researchers explain, which increases the likelihood of WNV infection reaching the brain and causing severe outcomes.
“Because the rapid production of neutralizing and inhibitory antibodies is essential for limiting WNV replication and dissemination, even a modest delay in the kinetics of the humoral response in elderly persons could increase susceptibility to virus infection,” they explain, adding:
“As functional deficits in the cells that coordinate early adaptive immune response and the lymph node microenvironment exist, strategies to correct these defects in at-risk individuals could improve responses to vaccines and limit replication of microbes that promote rapid disease pathogenesis.”
Earlier this month, the National Institutes of Health announced that an experimental vaccine for WNV is to enter human trials.