For older people, who account for a large number of severe cases and deaths caused by West Nile virus (WNV), the virus is particularly dangerous. WNV infection becomes serious when the virus crosses the blood-brain-barrier and runs amuck through nerve cells in the brain.
Several critical components of the early immune response to the virus are impaired in elderly individuals, a new study suggests, and goes on to say that this can explain the elderly’s vulnerability.
The immune response to WNV infection in four-month-old (the equivalent of young adults) and 18-month-old (elderly) mice was analyzed and compared by Michael Diamond, from Washington University in Saint Louis and colleagues. The older mice were more than three times as likely to die after WNV infection.
When the researchers assessed the amount of virus present in different tissues, they discovered that, in addition to more virus in their blood and spleens, the older mice had 20-fold higher virus levels in their brains—which likely causes the excess deaths.
After the transmission by mosquitoes, early specific immune response to WNV is believed to be dominated by antibodies. Consistent with this, the researchers found that older mice had less potent WNV-specific antibody responses in the early phase of infection.
The older mice also had weaker long-term antibody memory responses.
Antibody responses are kicked off in lymph nodes near the site of initial infection, known as draining lymph nodes, or DLNs, where antigen-presenting cells, helper T-cells, and antibody-producing B cells migrate to and interact to form so-called “germinal centers” and produce a highly specific antibody response.
In the older mice, the researchers discovered, germinal center formation was delayed, consistent with the blunted early antibody response.
Analyzing the DLNs in more details, they found that fewer helper T cells were present, suggesting that these cells from older mice are less capable of “trafficking” to the lymph nodes.
Experiments in which the researchers transplanted helper T cells from young adults or older mice into young adult recipients, and then followed them by live microscopy, demonstrated that this was because of reduced migratory ability of the helper T cells themselves.
Researchers additionally found that the lymph node environment in older mice had lower levels of immune stimulators, known as chemokines, and so was less able to attract the other immune cells needed for germinal center formation.
The authors conclude that their study identifies a series of key early defects associated with immune responses in old animals.
Regarding the mechanisms, they say “the delayed antibody and germinal center cell responses are due to trafficking defects, which are compounded by lower levels of chemokines in the lymph node after infection. Ultimately, this leads to blunted adaptive immune responses, higher viral titers, and increased death after West Nile virus infection.”
Illustration: Naïve CD4+ T cells from adult (green) or old (blue) mice were transferred into recipient mice. Cellular migration was tracked in an inflamed lymph node via intravital two-photon microscopy with blood vessels labeled in red. Credit: Grzegorz Gmyrek, CC-BY