Recent outbreaks of emerging viruses underscore the necessity of society-level commitments to research and development. In particular, research into how these threats function at the molecular level is imperative, and leveraging these advances towards the development of countermeasures is the obvious next step. If global trends in climate change, economic growth, and population expansion continue, human exposure will only increase. The 2015-2016 epidemic of Zika virus (ZIKV) is a key example of this phenomenon. The rising frequency and severity of hantavirus outbreaks in Chile and Argentina can also be partially attributed to these forces.
Of particular interest is the emergent phenomenon of antibody-dependent enhancement (ADE). In ADE, cross-reactive immunoglobulin G (IgG) from a prior infection bind a related virus, fail to neutralize, and instead provide a mode of attachment allowing the novel virus to infect vulnerable cells through Fc-FcR interactions. During the 2015-2016 outbreak, ADE of dengue virus (DENV)-specific IgG was hypothesized as a mechanism through which ZIKV achieved a more widespread and severe pathogenicity. We were particularly interested in investigating ZIKV ADE in the context of mouse models of infection. Connecting these different properties in vitro and in vivo may allow us to predict if ADE exacerbates human disease. To that end, we examined the plasma of DENV- and West Nile virus (WNV)-infected blood donors. Compared to controls, DENV- and WNV-infected samples displayed significantly greater reactivity against ZIKV envelope (E) protein in ELISA. This increased binding also translated to dosage-mediated enhancement of ZIKV infectivity when tested in vitro. Stat2-/- mice injected with a pool of the most enhancing DENV+ plasma succumbed to ZIKV-infection at significantly higher rates compared to those injected with pooled control plasma. Mice receiving WNV-infected plasma displayed intermediate survival levels, coinciding with intermediate binding and enhancement data.
We were especially interested in how phylogenetics influences ADE, as immunity against several flaviviruses is highly seroprevalent in the populations of multiple European and Asian countries. Tick-borne encephalitis virus (TBEV) presented a unique opportunity to explore these questions, as TBEV is one of the most distantly related flaviviruses to ZIKV. Vaccines against TBEV are also in widespread use throughout Germany, Austria, Switzerland, and Lithuania. When we examined sera from TBEV vaccinees, we found widespread cross-reactivity against ZIKV, but intermediate enhancement of ZIKV infection in vitro and negligible enhancement in vivo.
Enhancement, though, is a complicating factor observed only rarely across the whole of single-stranded viral families. ADE is likely driven by conserved epitopes present on the glycoproteins of related viruses, but why and how it occurs in flaviviruses and not elsewhere is yet to be determined. To further characterize properties associated with conserved epitopes, we resolved to examine another viral genus responsible for semi-seasonal outbreaks in rural South America: orthohantaviruses. Conserved and specific epitopes on the envelope glycoproteins (GnGc) of the severely lethal orthohantaviruses, including Andes virus (ANDV), are understudied and could provide evidence for cross-neutralization. To test this, we generated 19 distinct monoclonal antibodies (mAbs) against ANDV GnGc using murine hybridoma technology. In characterizing these mAbs, we observed overall trends in and correlations between specificity, epitope, neutralization, effector function, and protection against ANDV-induced disease in an animal model. These data suggest the existence of a wide array of neutralizing and protective antibody epitopes on hantavirus GnGc with unique properties and mechanisms of action.
Overall, the data presented here give definition to the relationship between reactivity against envelope glycoproteins, enhancement, neutralization, and protection in the context of these two emerging viral families. This knowledge will also drive innovation towards therapeutics and vaccines to help combat these imminent viral threats.
|Commitee:||Fernandez-Sesma, Ana, Simon, Viviana, Bogunovic, Dusan, Lee, Benhur, Klein, Sabra|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Subjects:||Virology, Immunology, Microbiology|
|Keywords:||Andes virus, Antibodies, Antibody-dependent enhancement, Hantavirus, Humoral immunity, Zika virus|
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