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Zika virus (ZIKV) causes microcephaly, whereas other related pathogenic flaviviruses do not. To reach the fetal brain, a virus must be transported from the maternal to the fetal circulation, which requires crossing of the placental barrier. This study demonstrates that ZIKV, but not two other globally relevant flaviviruses, efficiently infects fetal endothelial cells, a key component of the placental barrier, because only ZIKV can efficiently use the cell-surface receptor AXL. This paper also shows that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells.

AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses. PNAS doi: 10.1073/pnas.1620558114
Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.


Tagged: Biology, Emerging disease, Flavivirus, Microbiology, receptor, Science, Virology, virus
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Zika virus cannot replicate in mice – unless you knock out the mouse type I interferon with antibodies. As we know, Zika can replicate all too well in humans, but the pathogenesis and cell tropism of this troubling virus is not well understood. This new paper shows that there are important differences in the original African strains of Zika virus and the strains which have spread around the world recently. Understanding these differences might help us explain why this troublesome virus seemingly emerged out of nowhere to cause so much grief.

Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells. (2017) PLoS Pathog 13(2): e1006164. doi: 10.1371/journal.ppat.1006164
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that, upon congenital infection, can cause severe neonatal birth defects. To better understand the early innate immune response to ZIKV, we compared infection of human dendritic cells (DCs) between a contemporary Puerto Rican isolate and historic isolates from Africa and Asia. Human DCs supported productive replication following infection with the contemporary strain and exhibited donor variability in viral replication, but not viral binding. While contemporary and historic Asian lineage viruses replicated similarly, the African strains displayed more rapid replication kinetics with higher infection magnitude and uniquely induced cell death. Minimal DC activation and antagonism of type I interferon (IFN) translation was observed during ZIKV infection, despite strong induction of IFNB1 transcription and translation of other antiviral effector proteins. Treatment with a RIG-I agonist potently blocked ZIKV replication in human DCs, while type I IFN treatment was significantly less effective. Mechanistically, all ZIKV strains inhibited type I IFN receptor signaling through blockade of STAT1 and STAT2 phosphorylation. Altogether, we found that while ZIKV efficiently evades type I IFN responses during infection of human DCs, RIG-I signaling remains capable of inducing a strong antiviral state.


Tagged: arbovirus, Biology, Emerging disease, interferon, Microbiology, Science, Virology, virus
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Dengue has represented a significant public health burden for a number of decades. Given the lack of dengue-specific drugs and limited availability of licensed vaccine, new methods for prevention and control are urgently needed. Researchers investigated whether genetic manipulation of the mosquitoes’ native JAK/STAT pathway-mediated anti-DENV defense system could be used to render mosquitoes more resistant to infection. They generated Aedes aegypti mosquitoes overexpressing the JAK/STAT pathway components Dome and Hop under the control of a bloodmeal-inducible, fat body-specific vitellogenin promoter. These genetically modified mosquitoes showed an increased resistance to DENV infection, likely because of higher expression of DENV restriction factors and lower expression of DENV host factors, as indicated by transcriptome analyses. Expression of the transgenes had a minimal impact on mosquito longevity; however, it significantly impaired the mosquitoes’ fecundity. Bloodmeal-inducible fat body-specific overexpression of either Hop or Dome did not affect mosquito permissiveness to either ZIKV or CHIKV infection, suggesting a possible specialization of JAK/STAT pathway antiviral defenses. This is the first to provide a proof-of-concept that genetic engineering of the mosquitoes’ JAK/STAT immune pathway can be used to render this host more resistant to DENV infection.

Engineered Aedes aegypti JAK/STAT Pathway-Mediated Immunity to Dengue Virus. (2017) PLoS Negl Trop Dis 11(1): e0005187. doi: 10.1371/journal.pntd.0005187
We have developed genetically modified Ae. aegypti mosquitoes that activate the conserved antiviral JAK/STAT pathway in the fat body tissue, by overexpressing either the receptor Dome or the Janus kinase Hop by the blood feeding-induced vitellogenin (Vg) promoter. Transgene expression inhibits infection with several dengue virus (DENV) serotypes in the midgut as well as systemically and in the salivary glands. The impact of the transgenes Dome and Hop on mosquito longevity was minimal, but it resulted in a compromised fecundity when compared to wild-type mosquitoes. Overexpression of Dome and Hop resulted in profound transcriptome regulation in the fat body tissue as well as the midgut tissue, pinpointing several expression signatures that reflect mechanisms of DENV restriction. Our transcriptome studies and reverse genetic analyses suggested that enrichment of DENV restriction factor and depletion of DENV host factor transcripts likely accounts for the DENV inhibition, and they allowed us to identify novel factors that modulate infection. Interestingly, the fat body-specific activation of the JAK/STAT pathway did not result in any enhanced resistance to Zika virus (ZIKV) or chikungunya virus (CHIKV) infection, thereby indicating a possible specialization of the pathway’s antiviral role.


Tagged: Biology, dengue, Microbiology, mosquito, Science, Virology, virus
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Siderophores are small molecular iron chelators that are produced by microbes and whose most notable function is to sequester iron from the host and provide this essential metal nutrient to microbes. Recent studies have proposed additional, noncanonical roles for siderophores, including the acquisition of noniron metals and modulation of host functions. Recently, siderophores secreted by Klebsiella pneumoniae during lung infection have been shown to induce stabilization of the transcription factor HIF-1α, increase the expression of proinflammatory cytokines in the lung, and promote dissemination of K. pneumoniae to the spleen. Thus, their study demonstrated novel roles for siderophores in vivo, beyond iron sequestration. The interaction of siderophores with host cells further promotes the pathogenicity of K. pneumoniae and is likely relevant for other pathogens that also secrete siderophores in the host.

Siderophores: More than Stealing Iron. MBio. 2016 Nov 15;7(6). pii: e01906-16. doi: 10.1128/mBio.01906-16


Tagged: Bacteria, Biology, Microbiology, Science
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