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mSphere. 2018 Mar 28;3(2). pii: e00120-18. doi: 10.1128/mSphereDirect.00120-18. eCollection 2018 Mar-Apr.

Zika Virus Infection Preferentially Counterbalances Human Peripheral Monocyte and/or NK Cell Activity.

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Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
Centre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
National Institute of Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, United Kingdom.
Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
Communicable Diseases Centre, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.


Zika virus (ZIKV) has reemerged in the population and caused unprecedented global outbreaks. Here, the transcriptomic consequences of ZIKV infection were studied systematically first in human peripheral blood CD14+ monocytes and monocyte-derived macrophages with high-density RNA sequencing. Analyses of the ZIKV genome revealed that the virus underwent genetic diversification, and differential mRNA abundance was found in host cells during infection. Notably, there was a significant change in the cellular response, with cross talk between monocytes and natural killer (NK) cells as one of the highly identified pathways. Immunophenotyping of peripheral blood from ZIKV-infected patients further confirmed the activation of NK cells during acute infection. ZIKV infection in peripheral blood cells isolated from healthy donors led to the induction of gamma interferon (IFN-γ) and CD107a-two key markers of NK cell function. Depletion of CD14+ monocytes from peripheral blood resulted in a reduction of these markers and reduced priming of NK cells during infection. This was complemented by the immunoproteomic changes observed. Mechanistically, ZIKV infection preferentially counterbalances monocyte and/or NK cell activity, with implications for targeted cytokine immunotherapies. IMPORTANCE ZIKV reemerged in recent years, causing outbreaks in many parts of the world. Alarmingly, ZIKV infection has been associated with neurological complications such as Guillain-Barré syndrome (GBS) in adults and congenital fetal growth-associated anomalies in newborns. Host peripheral immune cells are one of the first to interact with the virus upon successful transmission from an infected female Aedes mosquito. However, little is known about the role of these immune cells during infection. In this work, the immune responses of monocytes, known target cells of ZIKV infection, were investigated by high-density transcriptomics. The analysis saw a robust immune response being elicited. Importantly, it also divulged that monocytes prime NK cell activities during virus infection. Removal of monocytes during the infection changed the immune milieu, which in turn reduced NK cell stimulation. This study provides valuable insights into the pathobiology of the virus and allows for the possibility of designing novel targeted therapeutics.


NK cells; RNA-seq; Zika virus; immune response; monocytes; transcriptomes

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