Effects of food supplementation and helminth removal on space use and spatial overlap in wild rodent populations.

Animal space use and spatial overlap can have important consequences for population-level processes such as social interactions and pathogen transmission. Identifying how environmental variability and inter-individual variation affect spatial patterns and in turn influence interactions in animal populations is a priority for the study of animal behaviour and disease ecology. Environmental food availability and macroparasite infection are common drivers of variation, but there are few experimental studies investigating how they affect spatial patterns of wildlife. Bank voles (Clethrionomys glareolus) are a tractable study system to investigate spatial patterns of wildlife and are amenable to experimental manipulations. We conducted a replicated, factorial field experiment in which we provided supplementary food and removed helminths in vole populations in natural forest habitat and monitored vole space use and spatial overlap using capture-mark-recapture methods. Using network analysis, we quantified vole space use and spatial overlap. We compared the effects of food supplementation and helminth removal and investigated the impacts of season, sex and reproductive status on space use and spatial overlap. We found that food supplementation decreased vole space use while helminth removal increased space use. Space use also varied by sex, reproductive status and season. Spatial overlap was similar between treatments despite up to threefold differences in population size. By quantifying the spatial effects of food availability and macroparasite infection on wildlife populations, we demonstrate the potential for space use and population density to trade-off and maintain consistent spatial overlap in wildlife populations. This has important implications for spatial processes in wildlife including pathogen transmission.

Isolation and characterization of a naturally occurring multidrug-resistant strain of the canine hookworm, Ancylostoma caninum.

Soil-transmitted nematodes infect over a billion people and place several billion more at risk of infection. Hookworm disease is the most significant of these soil-transmitted nematodes, with over 500 million people infected. Hookworm infection can result in debilitating and sometimes fatal iron-deficiency anemia, which is particularly devastating in children and pregnant women. Currently, hookworms and other soil-transmitted nematodes are controlled by administration of a single dose of a benzimidazole to targeted populations in endemic areas. While effective, people are quickly re-infected, necessitating frequent treatment. Widespread exposure to anthelmintic drugs can place significant selective pressure on parasitic nematodes to generate resistance, which has severely compromised benzimidazole anthelmintics for control of livestock nematodes in many areas of the world. Here we report, to our knowledge, the first naturally occurring multidrug-resistant strain of the canine hookworm Ancylostoma caninum. We reveal that this isolate is resistant to fenbendazole at the clinical dosage of 50 mg/kg for 3 days. Our data shows that this strain harbors a fixed, single base pair mutation at amino acid 167 of the ß-tubulin isotype 1 gene, and by using CRISPR/Cas9 we demonstrate that introduction of this mutation into the corresponding amino acid in the orthologous ß-tubulin gene of Caenorhabditis elegans confers a similar level of resistance to thiabendazole. We also show that the isolate is resistant to the macrocyclic lactone anthelmintic ivermectin. Understanding the mechanism of anthelmintic resistance is important for rational design of control strategies to maintain the usefulness of current drugs, and to monitor the emergence of resistance. The isolate we describe represents the first multidrug-resistant strain of A. caninum reported, and our data reveal a resistance marker that can emerge naturally in response to heavy anthelminthic treatment.

Dicer-2 Regulates Resistance and Maintains Homeostasis against Zika Virus Infection in Drosophila.

Zika virus (ZIKV) outbreaks pose a massive public health threat in several countries. We have developed an in vivo model to investigate the host-ZIKV interaction in Drosophila We have found that a strain of ZIKV replicates in wild-type flies without reducing their survival ability. We have shown that ZIKV infection triggers RNA interference and that mutating Dicer-2 results in enhanced ZIKV load and increased susceptibility to ZIKV infection. Using a flavivirus-specific Ab, we have found that ZIKV is localized in the gut and fat body cells of the infected wild-type flies and results in their perturbed homeostasis. In addition, Dicer-2 mutants display severely reduced insulin activity, which could contribute toward the increased mortality of these flies. Our work establishes the suitability of Drosophila as the model system to study host-ZIKV dynamics, which is expected to greatly advance our understanding of the molecular and physiological processes that determine the outcome of this disease.

Human interleukin-34-derived macrophages have increased resistance to HIV-1 infection.

The establishment of latent HIV-1 reservoirs in terminally differentiated cells represents a major impediment to the success of antiretroviral therapies. Notably, macrophages (Mϕs) are susceptible to HIV-1 infection and recent evidence suggests that they may be involved in long-term HIV-1 persistence. While the extensive functional heterogeneity seen across the Mϕ cell lineage parallels the spectrum of HIV-1 susceptibility reported across these cell subsets, the facets of Mϕ HIV-1 resistance and susceptibility remain to be fully defined. Notably, the differentiation of most Mϕ subsets depends on signaling through the macrophage colony-stimulating factor receptor (M-CSFR), which in addition to M-CSF, is now known to bind the unrelated interleukin-34 (IL-34) cytokine. The biological need for two M-CSFR ligands awaits full elucidation. Here, we report that Mϕs differentiated from human peripheral blood monocytes with IL-34 are substantially more resistant to HIV-1 infection than M-CSF-derived Mϕs. Moreover, while both Mϕ subsets express comparable surface protein levels of the HIV-1 receptor and co-receptor, CD4 and CCR5 respectively, the IL-34-Mϕs express significantly greater levels of pertinent restriction factor genes, potentially accounting for their greater resistance to HIV-1 infection than that observed in M-CSF-Mϕs. Together, our findings underline previously unexplored differentiation pathways resulting in HIV-1-susceptible and resistant Mϕ subsets and pave the way for further research that may overcome one of the last major hurdles in developing more successful antiretroviral therapy.

Biomimetic Placenta-Fetus Model Demonstrating Maternal-Fetal Transmission and Fetal Neural Toxicity of Zika Virus.

Recent global epidemics of viral infection such as Zika virus (ZIKV) and associated birth defects from maternal-fetal viral transmission highlights the critical unmet need for experimental models that adequately recapitulates the biology of the human maternal-fetal interface and downstream fetal development. Herein, we report an in vitro biomimetic placenta-fetus model of the maternal-fetal interface and downstream fetal cells. Using a tissue engineering approach, we built a 3D model incorporating placental trophoblast and endothelial cells into an extracellular matrix environment and validated formation of the maternal-fetal interface. We utilized this model to study ZIKV exposure to the placenta and neural progenitor cells. Our results indicated ZIKV infects both trophoblast and endothelial cells, leading to a higher viral load exposed to fetal cells downstream of the barrier. Viral inhibition by chloroquine reduced the amount of virus both in the placenta and transmitted to fetal cells. A sustained downstream neural cell viability in contrast to significantly reduced viability in an acellular model indicates that the placenta sequesters ZIKV consistent with clinical observations. These findings suggest that the placenta can modulate ZIKV exposure-induced fetal damage. Moreover, such tissue models can enable rigorous assessment of potential therapeutics for maternal-fetal medicine.

Is Nocturnal Foraging in a Tropical Bee an Escape From Interference Competition?

Temporal niche partitioning may result from interference competition if animals shift their activity patterns to avoid aggressive competitors. If doing so also shifts food sources, it is difficult to distinguish the effects of interference and consumptive competition in selecting for temporal niche shift. Bees compete for pollen and nectar from flowers through both interference and consumptive competition, and some species of bees have evolved nocturnality. Here, we use tropical forest canopy towers to observe bees (the night-flying sweat bees Megalopta genalis and M. centralis [Halictidae], honey bees, and stingless bees [Apidae]) visiting flowers of the balsa tree (Ochroma pyramalidae, Malvaceae). Because Ochroma flowers are open in the late afternoon through the night we can test the relative influence of each competition type on temporal nice. Niche shift due to consumptive competition predicts that Megalopta forage when resources are available: from afternoon into the night. Niche shift due to interference competition predicts that Megalopta forage only in the absence of diurnal bees. We found no overlap between diurnal bees and Megalopta in the evening, and only one instance of overlap in the morning, despite the abundance of pollen and nectar in the late afternoon and evening. This supports the hypothesis that Megalopta are avoiding interference competition, but not the hypothesis that they are limited by consumptive competition. We propose that the release from interference competition enables Megalopta to provision cells quickly, and spend most of their time investing in nest defense. Thus, increases in foraging efficiency directly resulting from temporal shifts to escape interference competition may indirectly lead to reduced predation and parasitism.

T-cell Responses in Individuals Infected with Zika Virus and in Those Vaccinated Against Dengue Virus.

BACKGROUND: The outbreak of Zika virus (ZIKV) infection in Brazil has raised concerns that infection during pregnancy could cause microcephaly and other severe neurodevelopmental malformations in the fetus. The mechanisms by which ZIKV causes fetal abnormalities are largely unknown. The importance of pre-infection with dengue virus (DENV), or other flaviviruses endemic to Brazil, remains to be investigated. It has been reported that antibodies directed against DENV can increase ZIKV infectivity by antibody dependent enhancement (ADE), suggesting that a history of prior DENV infection might worsen the outcome of ZIKV infection. METHODS: We used bioinformatics tools to design 18 peptides from the ZIKV envelope containing predicted HLA-I T-cell epitopes and investigated T-cell cross-reactivity between ZIKV-infected individuals and DENV-vaccinated subjects by IFNγ ELISPOT. RESULTS: Three peptides induced IFNγ production in both ZIKV-infected subjects and in DENV-vaccinated individuals. Flow cytometry indicated that 1 ZIKV peptide induced a CD4+ T-cell response in DENV-vaccinated subjects. CONCLUSIONS: We demonstrated that vaccination against DENV induced a T-cell response against ZIKV and identified one such CD4+ T-cell epitope. The ZIKV-reactive CD4+ T cells induced by DENV vaccination and identified in this study could contribute to the appearance of cross-reactive antibodies mediating ADE.