Abstract
The consequences of simultaneous infection with Zika (ZIKV) and Dengue (DENV) viruses are poorly understood. Here we show that rhesus macaques experimentally coinfected simultaneously with ZIKV and DENV-2 demonstrated ZIKV or DENV replication without an enhancement of either infection. Coinfection was accompanied by an increase in the proportions of CD14+CD16+ pro-inflammatory subsets of monocytes and release of pro-inflammatory cytokines in the plasma. Numerous cytokines such as I-TAC, Eotaxin, RANTES, MCP-1, IFNγ and MIG demonstrated a biphasic peak that coincided with the differences in kinetics of ZIKV and DENV replication suggesting that viral replication likely differentially modulated the release of these cytokines. Red blood cell indices significantly declined during acute infection suggesting transient anemia, and was accompanied by elevated levels of muscle, liver and renal injury markers. These findings have implications for understanding the pathogenesis of coinfection in ZIKV and DENV endemic regions, and is the 1st report of an experimental coinfection using the rhesus macaque model for ZIKV and DENV infections.
Highlights
The potential for ADE has been well documented following secondary exposure to a heterologous serotype of DENV, little is known about the pathogenic outcome of simultaneous infection with ZIKV and DENV
We have previously shown that prior exposure to ZIKV significantly enhanced DENV-2 viremia in rhesus macaques that was associated with high levels of DENV binding non-cross-neutralizing antibodies induced by ZIKV10,21
Our results showed that ZIKV viral loads peaked at 5 logs/ml of plasma at day 3 post-infection (PI) whereas DENV-2 viral loads peaked at 4 logs/ml of plasma as reported previously[10] suggesting that coinfection did not have a substantial effect on the replication kinetics of both viruses
Summary
The potential for ADE has been well documented following secondary exposure to a heterologous serotype of DENV, little is known about the pathogenic outcome of simultaneous infection with ZIKV and DENV. Aedes aegypti mosquitoes were shown to be infected with both ZIKV and DENV and capable of transmiting these viruses simultaneously suggesting that there is a potential for mosquitoes to transmit both viruses at the same time to the human host[14]. Approximately 27% of arbovirus infected human subjects examined in Nicaragua were found to be viremic for ZIKV, DENV and CHIKV16. We sought to address this gap in our knowledge using the rhesus macaque model[10,21,23,24,25,26,27,28,29] where we infected macaques with both ZIKV and DENV-2 simultaneously and assessed the effect on the kinetics of plasma virema, plasma cytokine levels, and monocyte/macrophage activation. Acute viremia was associated with activation of monocyte/macrophage subsets and release of numerous pro-inflammatory mediators that have implications for pathogenesis in the coinfected host
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