A phenomenon known as antibody-dependent enhancement, whereby previous infection by a different serotype of the same virus increases their infectivity, can seriously increase the vulnerability of individuals to some viral infections. In a recent study published in Science, a group demonstrated that this phenomenon may seriously impact individuals at risk of contracting the Zika virus if they were previously infected with Dengue or West Nile.
Zika Virus (ZIKV) is a single-stranded RNA virus belonging to the genus of Flaviviruses, which have the common characteristic of being transmitted to humans via mosquitos. This infection has drawn a lot of attention recently due to the epidemic outbreaks in southern-American regions such as Brazil, Central America and even some U.S. territories as well as the consequential microcephaly in newborn progenies of infected individuals. Other well-known and closely related viruses include Dengue Virus (DENV) and West Nile Virus (WNV). Notably, ZIKV, DENV and WNV are endemic in overlapping geographical areas and thus, many individuals may be infected with more than one of these viruses at different times in their lives, raising questions about the host immune response to viral infections in this unique context.
A particular concern is a phenomenon known as Antibody-Dependent Enhancement (ADE). Indeed, viruses rely on the selective interaction between their own proteins and cell surface ligands. Thus, cell types that do not express this ligand should be protected from infection. However, if an individual was previously infected with a different serotype of the same virus or a closely related virus, the antibodies produced by the immune system may be able to promote infection of these protected cell types. This rather counterintuitive outcome, where antibodies promote infectivity, is rendered possible by the ability of the antibody to act as a bridging platform between the target cell (bound via a surface receptor) and the viral particle (bound via the antigen). Specifically for ZIKV, previous studies demonstrated that in vitro, DENV antibodies promote ADE of ZIKV infection, but these findings were not corroborated in vivo.
To further study the relevance of this phenomenon in the context of ZIKV infection, a group of American researchers led by Dr. Lim investigated the in vitro and in vivo impact of DENV or WNV infection on subsequent ZIKV infection severity. Their findings were recently published in the prestigious journal Science. They started by looking at the ability of plasma from DENV (n=141) or WNV infected (n=146) individuals to bind a ZIKV specific antigen known as E protein by ELISA. Strikingly, plasma from DENV and WNV infected individuals respectively had a three and two-fold higher propensity to bind ZIKV E protein. Accordingly, a cell-based assay to monitor ADE demonstrated that cells co-treated with the plasma of DENV or WNV infected individuals were respectively 4 and 2-fold more susceptible to ZIKV infection. Next, the authors demonstrated that, as expected, this increases infectivity was solely dependent on the specific interaction between plasma IgGs and a cell-surface receptor known as FcγRII. Indeed, purified IgGs alone were able to mediate ADE and chemical or antibody blockade of FcγRII impaired ADE.
To validate the impact of their findings in vivo, the authors used a mouse model. Strikingly, mice previously injected with a small amount of plasma from DENV or WNV infected donors showed a very poor survival of 21% and 60%, respectively, compared to 93% for control mice. They also exhibited severe neurological symptoms such as paralysis. Moreover, tissues known to be affected by ZIKV symptoms, such as the spinal cord and testes, had increased viral titers, whereas other tissues did not. Finally, perhaps one of the most interesting, but yet intriguing, finding of their research is that the plasma dose administered can have completely opposite effects, with small doses yielding ADE and higher doses imparting a protective effect on ZIKV infection.
In summary, this study is the first to report a convincing ADE of ZIKV infection following DENV or WNV infection both in vitro and in vivo. The authors suggest that a few distinguishing features of their study, including plasma dosage and the use of polyclonal antibodies, allowed them to capture these effects in vivo. Moreover, their results provide a plausible explanation for the nature of the geographical area initially affected by the outbreak of ZIKV infections: The endemic presence of other Flavivirus infections in countries such as Brazil might have set the stage for ZIKV infections to take over in this area and cause more severe clinical symptoms such as microcephaly. Moreover, their results raise concerns about the impact of DENV and WNV vaccination, which leads to the production of antibodies that cross-react with ZIKV antigens and may, in turn, induce ADE. However, this has yet to be tested experimentally and is highly speculative at this point.
Written By: Samuel Rochette M.Sc