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Wolbachia are the most widespread maternally-transmitted bacteria in the animal kingdom. Their global spread in arthropods and varied impacts on animal physiology, evolution, and vector control are in part due to parasitic drive systems that enhance the fitness of infected females, the transmitting sex of Wolbachia. Male killing is one common drive mechanism wherein the sons of infected females are selectively killed. Despite decades of research, the gene(s) underlying Wolbachia-induced male killing remain unknown. Here using comparative genomic, transgenic, and cytological approaches in fruit flies, we identify a candidate gene in the eukaryotic association module of Wolbachia prophage WO, termed WO-mediated killing (wmk), which transgenically causes male-specific lethality during early embryogenesis and cytological defects typical of the pathology of male killing. The discovery of wmk establishes new hypotheses for the potential role of phage genes in sex-specific lethality, including the control of arthropod pests and vectors.

Fungi can intervene in hosts’ brain function. In humans, they can drive neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. The mechanism underlying innate immunity to fungi is well-known and universally conserved downstream of shared Toll/TLR receptors, which via the adaptor MyD88 and the transcription factor Dif/NFκB, induce the expression of antimicrobial peptides (AMPs). However, in the brain, Toll-1 could also drive an alternative pathway via Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. Here, we show that exposure to the fungus Beauveria bassiana reduced fly life span, impaired locomotion and caused neurodegeneration. Beauveria bassiana entered the Drosophila  brain and induced the up-regulation of AMPs , and the Toll adaptors wek and sarm , within the brain. RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana- induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause neuronal loss in the absence of infection. Thus, B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. A similar activation of Sarm downstream of TLRs upon fungal infections could underlie psychiatric and neurodegenerative diseases in humans.

The innate immune system provides hosts with a crucial first line of defense against pathogens. While immune genes are often among the fastest evolving genes in the genome, in Drosophila , antimicrobial peptides (AMPs) are notable exceptions. Instead, AMPs may be under balancing selection, such that over evolutionary timescales, multiple alleles are maintained in populations. In this study, we focus on the Drosophila AMP Diptericin A, which has a segregating amino acid polymorphism associated with differential survival after infection with the Gram-negative bacteria Providencia rettgeri . Diptericin A also helps control opportunistic gut infections by common Drosophila gut microbes, especially those of Lactobacillus plantarum . In addition to genotypic effects on gut immunity, we also see strong sex-specific effects that are most prominent in flies without functional diptericin A . To further characterize differences in microbiomes between different diptericin genotypes, we used 16S metagenomics to look at the microbiome composition. We used both lab-reared and wild-caught flies for our sequencing and looked at overall composition as well as the differential abundance of individual bacterial families. Overall, we find flies that are homozygous for one allele of diptericin A are better equipped to survive a systemic infection from P. rettgeri , but in general have a shorter lifespans after being fed common gut commensals. Our results suggest a possible mechanism for the maintenance of genetic variation of diptericin A through the complex interactions of sex, systemic immunity, and the maintenance of the gut microbiome.

Wolbachia pipientis is a maternally transmitted endosymbiont infecting more than half of terrestrial arthropod species. Wolbachia can express parasitic phenotypes such as manipulation of host reproduction and mutualist phenotypes such as protection against RNA virus infections. Because Wolbachia can invade populations by reproductive manipulation and block virus infection, it is used to modify natural insect populations. However, the ecological importance of virus protection is not yet clear, especially due to scarce information on Wolbachia protection against viruses that are common in nature. We used systemic infection to investigate whether Wolbachia protects its host by suppressing the titer of DMELDAV and DMelNora virus, two viruses that commonly infect Drosophila melanogaster flies in natural populations. Antiviral protection was tested in three systems to assess the impact of Wolbachia strains across species: (1) a panel of Wolbachia strains transfected into Drosophila simulans , (2) two Wolbachia strains introgressed into the natural host D. melanogaster , and (3) two native Wolbachia strains in their natural hosts Drosophila baimaii and Drosophila tropicalis . We showed that certain Wolbachia strains provide protection against DMelNora virus and DMELDAV, and this protection is correlated with Wolbachia density, which is consistent with what has been observed in protection against other RNA viruses. Additionally, we found that Wolbachia does not protect its original host, D. melanogaster , from DMELDAV infection. While native Wolbachia can reduce DMELDAV titers in D. baimaii , this effect was not detected in D. tropicalis . Although the Wolbachia protection-induced phenotype seems to depend on the virus, the specific Wolbachia strain, and the host species, our findings suggest that antiviral protection may be one of the mutualistic effects that helps explain why Wolbachia is so widespread in arthropod populations.

Wolbachia pipientis from Drosophila melanogaster (wMel) is an endosymbiotic bacterium that restricts transmission of human pathogenic flaviviruses and alphaviruses, including dengue, Zika, and chikungunya viruses, when introduced into the mosquito vector Aedes aegypti. To date, wMel-infected Ae. aegypti have been released in field trials in 5 countries to evaluate the effectiveness of this strategy for disease control. Despite the success in establishing wMel-infected mosquitoes in wild populations, and the well-characterized antiviral capabilities of wMel, transinfecting different or additional Wolbachia strains into Ae. aegypti may improve disease impact, and perhaps more importantly, could provide a strategy to account for the possible evolution of resistant arboviruses. Here, we report the successful transinfection of Ae. aegypti with the Wolbachia strains wMelCS (D. melanogaster), wRi (D. simulans) and wPip (Culex quinquefasciatus) and assess the effects on Ae. aegypti fitness, cytoplasmic incompatibility, tissue tropism and pathogen blocking in a laboratory setting. The results demonstrate that wMelCS provides a similar degree of protection against dengue virus as wMel following an infectious blood meal, and significantly reduces viral RNA levels beyond that of wMel following a direct challenge with infectious virus in mosquitoes, with no additional fitness cost to the host. The protection provided by wRi is markedly weaker than that of wMelCS, consistent with previous characterisations of these lines in Drosophila, while wPip was found to substantially reduce the fitness of Ae. aegypti. Thus, we determine wMelCS as a key candidate for further testing in field-relevant fitness tests and viremic blood feeding challenges in a clinical setting to determine if it may represent an alternative Wolbachia strain with more desirable attributes than wMel for future field testing.

Diverse fungi have been historically vital reservoirs of drug discovery, providing life-saving pharmaceuticals. Many species of fungi, yeasts in particular, are highly resistant to radiation, with their cellular contents potentially conferring dietary radioresistance. We developed a Drosophila model to test whether feeding two highly radioresistant fungi, Aureobasidium pullulans and Rhodotorula taiwanensis, could improve fly lifespan and gut morphology after acute irradiation. We constructed a dosimetry curve for the lifespan response of males and females to irradiation and found dose-dependent and sex-specific effects on lifespan. We also determined that the sex-specific response to irradiation correlated with nuclear morphology defects in the gut, with the more radiosensitive males displaying increased midgut cellular holes and aberrant nuclear morphology. To determine if feeding Aureobasidium pullulans and Rhodotorula taiwanensis before irradiation could improve survival and gut morphology, we first exclusively fed males and females each fungus and observed that they tolerated the diet well. Using these methods, we found that only two days of pre-feeding Aureobasidium pullulans increased male lifespan, but not female, after irradiation, and improved nuclear morphology in the gut. However, dietary Rhodotorula taiwanensis was not protective. Overall, this study identified a highly radioresistant dietary fungus, Aureobasidium pullulans , as effective for extending male Drosophila lifespan and improving gut morphology following irradiation. Since the gut is particularly sensitive to the effects of irradiation, this fungus indicates a potential therapeutic for patients undergoing radiotherapy. Furthermore, this method could identify additional radioresistant fungi that protect the gut from radiation injury.

Wolbachia is an intracellular bacterium that infects a remarkable range of insect hosts. Insects such as mosquitos act as vectors for many devastating human viruses such as Dengue, West Nile, and Zika. Remarkably, Wolbachia infection provides insect hosts with resistance to many arboviruses thereby rendering the insects ineffective as vectors. To utilize Wolbachia effectively as a tool against vector-borne viruses a better understanding of the host-Wolbachia relationship is needed. To investigate Wolbachia-insect interactions we used the Wolbachia/Drosophila model that provides a genetically tractable system for studying host-pathogen interactions. We coupled genome-wide RNAi screening with a novel high-throughput fluorescence in situ hybridization (FISH) assay to detect changes in Wolbachia levels in a Wolbachia-infected Drosophila cell line JW18. 1117 genes altered Wolbachia levels when knocked down by RNAi of which 329 genes increased and 788 genes decreased the level of Wolbachia. Validation of hits included in depth secondary screening using in vitro RNAi, Drosophila mutants, and Wolbachia-detection by DNA qPCR. A diverse set of host gene networks was identified to regulate Wolbachia levels and unexpectedly revealed that perturbations of host translation components such as the ribosome and translation initiation factors results in increased Wolbachia levels both in vitro using RNAi and in vivo using mutants and a chemical-based translation inhibition assay. This work provides evidence for Wolbachia-host translation interaction and strengthens our general understanding of the Wolbachia-host intracellular relationship.

Host-microbe interactions are virtually bidirectional, but how the host affects their microbiome is poorly understood. Here, we report that the host is a critical modulator to regulate the lifestyle switch and pathogenicity heterogeneity of the opportunistic pathogens Serratia marcescens utilizing the Drosophila and bacterium model system. First, we find that Drosophila larvae efficiently outcompete S. marcescens and typically drive a bacterial switch from pathogenicity to commensalism toward the fly. Furthermore, Drosophila larvae reshape the transcriptomic and metabolic profiles of S. marcescens characterized by a lifestyle switch. More importantly, the host alters pathogenicity and heterogeneity of S. marcescens in the single-cell resolution. Finally, we find that larvae-derived AMPs are required to recapitulate the response of S. marcescens to larvae. Altogether, our findings provide an insight into the pivotal roles of the host in harnessing the life history and heterogeneity of symbiotic bacterial cells, advancing knowledge of the reciprocal relationships between the host and pathogen.

In the animal kingdom, nutritional mutualism is a perpetual and intimate dialogue carried out between the host and its associated gut community members. This dialogue affects many aspects of the host's development and physiology. Some constituents of the animal gut microbiota can stably reside within the host for years, and such long-term persistence might be a prerequisite for these microbes to assert their beneficial impact. How long-term persistence is established and maintained is an interesting question, and several classic model organisms associated with cultivable resident strains are used to address this question. However, in Drosophila, this model has long eluded fly geneticists. In this issue of PLOS Biology, Pais and colleagues present the most rigorous and comprehensive demonstration to date that persistence and gut residency do take place in the digestive tract of Drosophila melanogaster. This natural gut isolate of Acetobacter thailandicus stably colonizes the adult fly foregut, accelerates larval maturation, and boosts host fecundity and fertility as efficiently as the known laboratory strains. The discovery of such stable association will be a boon for the Drosophila community interested in host-microbiota interaction, as it not only provides a novel model to unravel the molecular underpinnings of persistence but also opens a new arena for using Drosophila to study the implications of gut persistence in evolution and ecology.

Drosophila melanogaster and its close relatives have been extremely important model species in the development of population genetic models that serve to explain patterns of diversity in natural populations, a major goal of evolutionary biology. A detailed picture of the evolutionary history of these species is beginning to emerge, as the relative importance of forces including demographic changes and natural selection is established. A continuing aim is to characterise levels of genetic diversity in a large number of populations of these species, covering a wide geographic area. We have used collections from five previously un-sampled wild populations of D. melanogaster and two of D. simulans, across three continents. We estimated levels of genetic diversity within, and divergence between, these populations, and looked for evidence of genetic structure both between ancestral and derived populations, and amongst derived populations. We also investigated the prevalence of infection with the bacterial endosymbiont Wolbachia. We found that D. melanogaster populations from Sub-Saharan Africa are the most diverse, and that divergence is highest between these and non-Sub-Saharan populations. There is strong evidence for structuring of populations between Sub-Saharan Africa and the rest of the world, and some evidence for weak structure amongst derived populations. Populations from Sub-Saharan Africa also differ in the prevalence of Wolbachia infection, with very low levels of infection compared to populations from the rest of the world.