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Global Zika virus (ZIKV) outbreaks and their strong link to microcephaly have raised major public health concerns. ZIKV has been reported to affect the innate immune responses in neural stem/progenitor cells (NS/PCs). However, it is unclear how these immune factors affect neurogenesis. In this study, we used Asian-American lineage ZIKV strain PRVABC59 to infect primary human NS/PCs originally derived from fetal brains. We found that ZIKV overactivated key molecules in the innate immune pathways to impair neurogenesis in a cell stage-dependent manner. Inhibiting the overactivated innate immune responses ameliorated ZIKV-induced neurogenesis reduction. This study thus suggests that orchestrating the host innate immune responses in NS/PCs after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology. Author summary: ZIKV has been reported to affect the innate immune responses in neural stem cells. We found that inhibiting the overactivated innate immune responses ameliorated Zika virus-induced neurogenesis reduction in human neural stem cells, which are the origin of the brain. This study suggests that coordinating the host innate immune responses in neural stem cells after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology. [ABSTRACT FROM AUTHOR]

Global Zika virus (ZIKV) outbreaks and their link to microcephaly have raised major public health concerns. However, the mechanism of maternal-fetal transmission remains largely unknown. In this study, we determined the role of yolk sac (YS) microglial progenitors in a mouse model of ZIKV vertical transmission. We found that embryonic (E) days 6.5-E8.5 were a critical window for ZIKV infection that resulted in fetal demise and microcephaly, and YS microglial progenitors were susceptible to ZIKV infection. Ablation of YS microglial progenitors significantly reduced the viral load in both the YS and the embryonic brain. Taken together, these results support the hypothesis that YS microglial progenitors serve as "Trojan horses," contributing to ZIKV fetal brain dissemination and congenital brain defects. Author summary: ZIKV is more likely to cause fetal demise and brain malformations when the mother is infected at an early stage of pregnancy, which is the critical time window when a special type of immune cells called microglia appear in the YS and migrate to the fetal brain. YS-derived microglia are susceptible to ZIKV infection and can act as "Trojan horses" to bring ZIKV from the mother to the fetal brain. [ABSTRACT FROM AUTHOR]

Dengue is the most common arboviral disease of humans. There is an unmet need for a therapeutic intervention that reduces the duration and severity of dengue symptoms and diminishes the likelihood of severe complications. To this end, there are active discovery efforts in industry and academia to develop interventions, with a focus on small molecule inhibitors of dengue virus replication that are suitable for therapy or chemoprophylaxis. Advancements in animal models of dengue virus infection together with the possibility of a dengue human infection model have further enhanced the platform for dengue drug discovery. Whilst drug discovery efforts gestate, there are ongoing clinical research designed to benefit today's patients, including trials of supportive care interventions, and descriptive studies that should improve the ability of clinicians to make an accurate diagnosis early in the illness course and to identify patients most at risk of progression to severe disease. This review provides a state of the art summary of dengue drug discovery, clinical trials, and supportive allied research and reflects discussions at the 2nd International Dengue Therapeutics Workshop held in Ho Chi Minh City, Vietnam, in December 2013. [ABSTRACT FROM AUTHOR]

The flavivirus NS5 harbors both a methyltransferase (MTase) and an RNA-dependent RNA polymerase (RdRP). Both enzyme activities of NS5 are critical for viral replication. Recently, the full-length NS5 crystal structure of Japanese encephalitis virus reveals a conserved MTase-RdRP interface that features two conserved components: a six-residue hydrophobic network and a GTR sequence. Here we showed for the first time that these key interface components are essential for flavivirus replication by various reverse genetics approaches. Interestingly, some replication-impaired variants generated a common compensatory NS5 mutation outside the interface (L322F), providing novel routes to further explore the crosstalk between MTase and RdRP. Author Summary: Flaviviruses, such as Japanese encephalitis virus (JEV) and dengue virus 1-4 (DENV1-4), are important arthropod-borne pathogens causing major public health threats worldwide. For example, JEV is the most common cause of viral encephalitis in eastern and southern Asia, affecting over 50,000 patients, and leads to 15,000 deaths annually. DENV is responsible for an estimated 50 million cases of dengue fever and over 450,000 cases of life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) each year. Currently, there is no effective antiviral therapeutics available for flaviviruses. Non-structural protein 5 (NS5) is a multifunctional, viral protein that contains a methyltransferase (MTase) and an RNA-dependent RNA polymerase (RdRP). Both MTase and RdRP are required for replication of the viral genome. A conserved interface between MTase and RdRP was first identified in the full-length NS5 crystal structure of JEV. In this study we used the infectious clones of both JEV and DENV-2 to perform functional mutagenesis analyses and demonstrated for the first time that the recently identified conserved interface between MTase and RdRP is critical for viral replication. In a replicon system, we also confirmed that mutations within the conserved interface greatly affect viral RNA replication during viral infection. Our functional validation of the conserved MTase-RdRP interface consolidated its potential as a novel target for anti-flavivirus drug development. [ABSTRACT FROM AUTHOR]

This article provides recommendations for the design and conduct of early-phase clinical trials for dengue therapeutics. The focus is on antiviral therapies, as they are the main area of drug development for dengue. The article discusses patient populations, diagnosis, safety signals, clinical and laboratory endpoints, virological endpoints, dosing and pharmacology, non-invasive physiological monitoring, and sample sizes for early-phase studies. The article acknowledges the challenges in developing therapies for dengue but provides a standardized reporting approach to accelerate clinical testing. [Extracted from the article]

Reference 1 Xu P, Shan C, Dunn TJ, Xie X, Xia H, Gao J, et al. (2020) Role of microglia in the dissemination of Zika virus from mother to fetal brain. The fourteenth author's name is spelled incorrectly. [Extracted from the article]