Though the symptoms of Zika virus (ZIKV) infections are generally mild, the virus can be devastating for expectant mothers. The mosquito-borne pathogen can be transmitted to the fetus, causing microcephaly—a severe and debilitating neurological birth defect. While case numbers have tapered off since the ZIKV epidemic of 2015, the hunt for ZIKV vaccines continues in anticipation of its likely resurgence.
The blueprints for an effective vaccine require an understanding of ZIKV’s modus operandi for escaping the host’s immune defenses, explained Lisa F.P. Ng, a Senior Principal Investigator at A*STAR’s Infectious Diseases Labs, and Singapore Immunology Network (SIgN). “What is the key mechanism by which ZIKV crosses the blood-brain barrier and placenta to infect the developing fetus? Are there any host or viral factors that allow ZIKV persistence in immune-privileged tissues such as the brain and the placenta?”
Ng led an international team that examined this complicated relationship between the virus and the immune system, using a mouse model of ZIKV infection. Two groups of ZIKV-infected mice were studied, one of which was treated with a monoclonal antibody to temporarily switch off type I interferon (IFN), a potent regulator of the immune system. Such IFN inhibition recapitulates the pathology of an active ZIKV infection in humans.
Using a suite of analytical techniques, including flow cytometry, immunoassays and viral neutralization tests, they found that IFN-suppressed animals displayed a significantly exaggerated immune response after ZIKV infection. These mice produced many more antibodies targeting the virus than the control cohort.
Interestingly, however, with IFN inhibition, it was a case of the bark being worse than the bite. There was an abundance of host antibodies that bound to ZIKV, but these neither inactivated the virus nor protected against infection. Further characterization of these epitopes revealed a detrimental role of these antibodies, as they shielded the viruses with harmless host antibodies to evade immune destruction.
“Due to the conformational nature of the virus, non-protective antibodies that are present and bound at a substantial level could hinder the binding of neutralizing antibodies to their epitopes,” Ng said.
Knowledge gained from this study could support the development of better vaccine candidates that elicit stronger targeted B-cell responses and avoid detrimental ones, Ng said. “Although ZIKV has fallen off the radar due to another unprecedented crisis resulting from a novel respiratory pathogen, families affected by ZIKV-related health issues would have to live with the effects for a very long time,” she said.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN), and the Institute of Molecular and Cell Biology (IMCB).
