Abstract
Little is known about the contribution of virus-specific and cross-reacting antibodies (Abs) or the cellular immune response generated by a primary dengue (DENV) infection on the course of a secondary zika (ZIKV) infection in vivo. Here we show that the length of time between DENV/ZIKV infections has a qualitative impact on controlling early ZIKV replication. Depletion of DENV2-specific Abs in sera confirmed that those type-specific Abs do not contribute to ZIKV control. We show that the magnitude and durability of the neutralizing antibodies (nAbs) induced by a secondary ZIKV infection is modest compared to the response induced after a secondary heterologous DENV infection. Our in vivo results are showing a complex interplay between the cellular and innate immune responses characterized by a high frequency of plasmacytoid dendritic cells (pDC) correlating with an increase in the frequency of DENV antigen specific T cells and a significant control of ZIKV replication which is time dependent. Taken together, our results suggest that early after ZIKV infection other mechanisms such as the innate and cellular immune responses may play a predominant role in controlling ZIKV replication. Regardless of the time elapsed between infections there was no evidence of in vivo antibody-dependent enhancement (ADE) of ZIKV by DENV immunity. These findings have pivotal implications while interpreting ZIKV pathogenesis in flavivirus-experimented populations, diagnostic results interpretation and vaccine designs and schedules among others.
Highlights
Zika virus (ZIKV) spread in the Americas has been linked to unique severe adverse outcomes such as fetal loss [1], congenital Zika syndrome (CZS) [2], Guillain-Barresyndrome (GBS) [3], and rare cases of encephalopathy [4], meningoencephalitis [5], myelitis [6], uveitis [7], and severe thrombocytopenia [8]
From our previous work in non-human primates and others using humans, we believe that previous DENV immunity confers some degree of protection against ZIKV infection
One is precisely if the time between primary DENV and a subsequent ZIKV infections may play a role in the degree of protection conferred by DENV immunity
Summary
Zika virus (ZIKV) spread in the Americas has been linked to unique severe adverse outcomes such as fetal loss [1], congenital Zika syndrome (CZS) [2], Guillain-Barresyndrome (GBS) [3], and rare cases of encephalopathy [4], meningoencephalitis [5], myelitis [6], uveitis [7], and severe thrombocytopenia [8]. Prior exposure to a single DENV serotype predisposes individuals to severe disease upon a secondary heterologous DENV infection, and the time interval between infections has been considered as a risk factor [17]. A short interval of time between homologous or heterologous DENV infections usually results in protection from disease, while an extended period of time is associated with the potential for severe dengue [18,19,20], due to either cross-reactive non-neutralizing antibodies (Abs) [21, 22] and cross-reacting T cells [23,24,25]. The association of previous flavivirus exposure at any time before ZIKV infection with the severe adverse outcomes of the infection is still unclear
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