Abstract
Dengue virus (DENV) is a mosquito-borne pathogen for which no vaccine or specific therapeutic is available. Although it is well established that dendritic cells and macrophages are primary sites of DENV replication, it remains unclear whether non-hematopoietic cellular compartments serve as virus reservoirs. Here, we exploited hematopoietic-specific microRNA-142 (miR-142) to control virus tropism by inserting tandem target sites into the virus to restrict replication exclusively in this cell population. In vivo use of this virus restricted infection of CD11b+, CD11c+, and CD45+ cells, resulting in a loss of virus spread, regardless of the route of administration. Furthermore, sequencing of the targeted virus population that persisted at low levels, demonstrated total excision of the inserted miR-142 target sites. The complete conversion of the virus population under these selective conditions suggests that these immune cells are the predominant sources of virus amplification. Taken together, this work highlights the importance of hematopoietic cells for DENV replication and showcases an invaluable tool for the study of virus pathogenesis.
Highlights
Dengue virus (DENV) is a mosquito-borne flavivirus and the etiological agent of dengue fever and the more severe clinical presentations known as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [1]
Dengue virus (DENV) is becoming a global threat as anthropogenic factors are increasing the prevalence of vector species capable of transmitting the pathogen
There are currently no vaccines or therapeutics against DENV, and the study of virus pathogenesis and dissemination has been largely limited to artificial mouse models
Summary
Dengue virus (DENV) is a mosquito-borne flavivirus and the etiological agent of dengue fever and the more severe clinical presentations known as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [1]. A heterotypic secondary infection with a different serotype can lead to more severe or fatal clinical manifestations such as DHF/DSS [7]. This pathogenesis feature is referred to as antibody-dependent enhancement, a phenomenon mediated by Fc receptors found on cells such as macrophages, neutrophils, and DCs [5,6,8]. Non-neutralizing antibodies against DENV during a heterotypic secondary infection allows for infectious immune complexes to enter Fc-receptor expressing cells and initiate replication, thereby enhancing virus growth within these cells [6]
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