Abstract
BackgroundThe emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in protecting hosts from ZIKV infection lies in the findings that ZIKV has evolved various strategies to subvert the host defense line by counteracting the early IFN induction or subsequent IFN signaling. Yet, mechanisms underlying the counter-IFN capability of ZIKV and its proteins, which might contribute to the well-recognized broad cellular tropisms and persistence of ZIKV, remain incompletely understood.ResultsUsing RNA sequencing-based transcriptional profiling of whole blood cells isolated from patients acutely infected by ZIKV, we found that transcriptional signature programs of antiviral interferon-stimulated genes and innate immune sensors in ZIKV-infected patients remained inactive as compared to those of healthy donors, suggesting that ZIKV was able to suppress the induction of IFN-I during the natural infection process in humans. Furthermore, by analyzing the molecular interaction in a ZIKV NS4A-overexpression system, or in the context of actual ZIKV infection, we identified that ZIKV NS4A directly bound MAVS and thereby interrupted the RIG-I/MAVS interaction through the CARD-TM domains, leading to attenuated production of IFN-I.ConclusionsOur findings collectively revealed that ZIKV NS4A targeted MAVS and contributed to ZIKV immune evasion through abrogating MAVS-mediated IFN production. These findings obtained from patient studies have added new knowledge and molecular details to our understanding regarding how ZIKV mediates suppression of the IFN-I system and may provide a new basis for the future development of anti-ZIKV strategies.
Highlights
The emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV
ZIKV suppresses type I interferon production in human subjects and in host cells To assess whether ZIKV infection influences the production of type I IFN in patients, we collected whole blood cells from ZIKV-infected human subjects and conducted RNA sequencing (RNA-seq)-based transcriptional profiling experiments to characterize the expression of type I IFN genes and their downstream ISGs
When HFF-1 cells were infected with ZIKV and the cell lysates were subsequently precipitated using an antibody against mitochondrial antiviral signaling (MAVS) to pull down its interacting proteins, our results revealed that an antibody against MAVS could pull down ZIKV NS4A (Fig. 3e), suggesting that NS4A and MAVS were complexed in ZIKV-infected cells
Summary
The emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. While ZIKV was originally identified in the Zika forest of Uganda in 1947 and the first human infection case was documented in 1954, the most serious Zika pandemic to date began in the Americas in 2013–2014 [1, 2]. Most Zika cases are asymptomatic or only manifest as an influenza-like illness, severe forms of ZIKV infection such as microcephaly and other neurological abnormalities in newborns and Guillain–Barré syndrome, meningoencephalitis, multi-organ failure or thrombocytopenia in adults are seen in the clinic [1, 4]. Understanding the molecular basis and host immune mechanisms based on which severe diseases develop as a result of ZIKV infection is key to developing strategies against ZIKV-associated conditions
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