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.
Seems like a great idea – the widespread use of insecticide coate bednets to cut the spread of malaria by mosquitoes (mostly active at night). Unfortunately nature is rarely that simple. Widespread use has driven mosquitoes to evolve resistance to the insecticides used. By identifying genetic patterns that predict when and where resistance will evolve, scientists hope to curb resistance.
Genomic Footprints of Selective Sweeps from Metabolic Resistance to Pyrethroids in African Malaria Vectors Are Driven by Scale up of Insecticide-Based Vector Control. (2017) PLoS Genet 13(2): e1006539. doi: 10.1371/journal. pgen.1006539
Malaria control currently relies heavily on insecticide-based vector control interventions. Unfortunately, resistance to insecticides threatens the continued effectiveness of these measures. Metabolic resistance, caused by increased detoxification of insecticides, presents the greatest threat to vector control, yet it remains unclear how these mechanisms are linked to underlying genetic changes driven by the massive selection pressure from these interventions, such as the widespread use of Long Lasting Insecticide Nets (LLINs) across Africa. Therefore, understanding the direction and speed at which this operationally important form of resistance spreads through mosquito populations is essential if we are to get ahead of the ‘resistance curve’ and avert a public health catastrophe. Here, using microsatellite markers, whole genome sequencing and fine-scale sequencing at a major resistance locus, we elucidated the Africa-wide population structure of Anopheles funestus, a major African malaria Vector, and detected a strong selective sweep occurring in a genomic region controlling cytochrome P450-based metabolic pyrethroid resistance in this species. Furthermore, we demonstrated that this selective sweep is driven by the scale-up of insecticide-based malaria control in Africa, highlighting the risk that if this level of selection and spread of resistance continues unabated, our ability to control malaria with current interventions will be compromised.
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.
Historically, bacteria have been thought of as simple cells whose only aim is to replicate. However, research over the past two decades has revealed that many types of bacteria are able to develop into communities that contain several types of cells, with different cell types performing particular roles. Streptomyces bacteria employ a newly-discovered cell type, the “explorer” cell, to rapidly colonize new areas in the face of competition. For decades, researchers have described Streptomyces colonies in terms of vegetative cells, aerial hyphae and spores. The explorer cells offer Streptomyces an alternative means of escape from their normal life cycle and local environment in the face of competition. This makes sens, given that Streptomyces lack the ability to move (“motility”) in the traditional sense (for example, by swimming or gliding). This discovery demonstrates a surprisingly dynamic strategy in which a ‘non-motile’ bacterium can use cues from other microbes, long-range signaling, and multicellularity to make a graceful exit when times get tough.
Bacteria: Exploring new horizons. (2017) eLife 6: e23624. doi: 10.7554/eLife.23624
Streptomyces exploration is triggered by fungal interactions and volatile signals. (2017) eLife 6: e21738. doi: 10.7554/eLife.21738
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.
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
More than 2 billion people around the world are infected with intestinal helminths, parasitic worms that can cause disease, complicate pregnancies, and stunt the growth of children. A number of drugs are currently used to treat hookworms, one of the most common helminths to infect humans, but many worry that prolonged use of the drugs could lead to drug-resistant worms. Now researchers have described a rapid test that can monitor hookworm DNA for drug resistance mutations.
Isothermal Diagnostic Assays for Monitoring Single Nucleotide Polymorphisms in Necator americanus Associated with Benzimidazole Drug Resistance. (2016) PLoS Negl Trop Dis 10(12): e0005113. doi: 10.1371/journal.pntd.0005113
Hookworms are amongst the major STHs and the second most prevalent intestinal hel- minth of humans. Large-scale treatment with the benzimidazoles (BZs) albendazole or mebendazole is the major control strategy against STHs in mass drug administration (MDA) programs. Prolonged and repeated treatment with the same anthelmintics has led to the emergence of widespread BZ resistance in veterinary parasites which is caused by a single nucleotide polymorphism at codon 200, 167 or 198 in the β-tubulin gene. There is a considerable concern that prolonged use of the same anthelmintics with suboptimal effi- cacy against hookworms, may select for resistant parasites and favour the development of resistance. We developed a novel genotyping assay to screen for β-tubulin polymorphisms in N. americanus, using the SmartAmp2 method. SmartAmp2 is a unique genotyping technology that detects a mutation under isothermal conditions with high specificity and sensitivity. The N. americanus SNP detection assay is rapid, sensitive and highly specific and has the potential to be used in the field for the detection of SNPs associated with BZ resistance.
Having been involved in microbiology for so long it’s sometimes difficult to see the progress we are making. When I started out as a microbiologist in the 1970s the impact of molecular biology on microbiology was overwhelming, even if it took us a few years to think about what we should do with our new tools beyond expressing foreign proteins in microbes. With the development of PCR in the 1980s the flood of new sequence data and new species increased, and the 1990s brought us into the genomics era with the start of the Human Genome Project. But around the millenium it all got a bit cloudy for me and I wasn’t sure where we were headed any longer.
Many people would argue that CRISPR has been the great leap forward of the last decade, but I’m not so sure. To me it’s just another tool, following on directly from cloning and PCR. When people involved the first human genome CRISPR trials tell you they are “a huge undertaking and not very scalable“, they may have a point. As the NHS crumbles in the UK, what hope will there ever be for rolling out such expensive technologies worldwide? Anyway, back ten years….
As we accummulated more and more metagenomes, I still wasn’t sure were we were going. Was this just stamp collecting? Of course I shouldn’t have worried, because blue skies research is never a waste. The true revalation of the past decade has been the link between gut bacteria and the brain – the real game changer (Gut Microbes and the Brain: Paradigm Shift in Neuroscience). Who could ever have seen that one coming? The news that Parkinson’s Disease may be triggered (in those with a genetic predisposition) by the balance and shifts of gut flora is the real future. Forget expensive genome engineering, the future worldwide looks like faecal transplants (in the short term) and diets, probiotics and pills of freeze dried bacteria in the medium term. This is already happening in clinics to treat C. difficile colitis and other bowel conditions, but extending these treatments to the brain is the early days of a revolution. Forget moonshot-scale expenditure, the future is all about the bugs in your gut. The future’s bright. The future’s brown.
Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 167(6): 1469–1480.e12, 1 December 2016. doi: 10.1016/j.cell.2016.11.018
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson’s disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.
The first available dengue vaccine, CYD-TDV (Dengvaxia), is estimated to reduce the burden of dengue and be potentially cost effective in settings where infections with dengue are common.
The Long-Term Safety, Public Health Impact, and Cost- Effectiveness of Routine Vaccination with a Recombinant, Live-Attenuated Dengue Vaccine (Dengvaxia): A Model Comparison Study. (2016) PLoS Med 13(11): e1002181. doi: 10.1371/journal.pmed.1002181
Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine. Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccine.