RESUMO
BACKGROUND: Innate immune responses can be activated by pathogen-associated molecular patterns (PAMPs), danger signals released by damaged tissues, or the absence of self-molecules that inhibit immunity. As PAMPs are typically conserved across broad groups of pathogens but absent from the host, it is unclear whether they allow hosts to recognize parasites that are phylogenetically similar to themselves, such as parasitoid wasps infecting insects. RESULTS: Parasitoids must penetrate the cuticle of Drosophila larvae to inject their eggs. In line with previous results, we found that the danger signal of wounding triggers the differentiation of specialized immune cells called lamellocytes. However, using oil droplets to mimic infection by a parasitoid wasp egg, we found that this does not activate the melanization response. This aspect of the immune response also requires exposure to parasite molecules. The unidentified factor enhances the transcriptional response in hemocytes and induces a specific response in the fat body. CONCLUSIONS: We conclude that a combination of danger signals and the recognition of nonself molecules is required to activate Drosophila's immune response against parasitic insects.
Assuntos
Hemócitos , Interações Hospedeiro-Parasita , Imunidade Inata , Vespas , Animais , Vespas/fisiologia , Interações Hospedeiro-Parasita/imunologia , Hemócitos/imunologia , Drosophila melanogaster/parasitologia , Drosophila melanogaster/imunologia , Drosophila melanogaster/fisiologia , Larva/imunologia , Larva/parasitologia , Drosophila/parasitologia , Drosophila/imunologiaRESUMO
Polymorphisms in immunity genes can have large effects on susceptibility to infection. To understand the origins of this variation, we have investigated the genetic basis of resistance to the parasitoid wasp Leptopilina boulardi in Drosophila melanogaster. We found that increased expression of the gene lectin-24A after infection by parasitic wasps was associated with a faster cellular immune response and greatly increased rates of killing the parasite. lectin-24A encodes a protein that is strongly up-regulated in the fat body after infection and localizes to the surface of the parasite egg. In certain susceptible lines, a deletion upstream of the lectin-24A has largely abolished expression. Other mutations predicted to abolish the function of this gene have arisen recurrently in this gene, with multiple loss-of-expression alleles and premature stop codons segregating in natural populations. The frequency of these alleles varies greatly geographically, and in some southern African populations, natural selection has driven them near to fixation. We conclude that natural selection has favored the repeated loss of an important component of the immune system, suggesting that in some populations, a pleiotropic cost to lectin-24A expression outweighs the benefits of resistance.
Assuntos
Parasitos , Vespas , Animais , Drosophila/genética , Drosophila melanogaster/genética , Interações Hospedeiro-Parasita , Vespas/fisiologia , Lectinas/genética , Seleção GenéticaRESUMO
Metagenomic studies have demonstrated that viruses are extremely diverse and abundant in insects, but the difficulty of isolating them means little is known about the biology of these newly discovered viruses. To overcome this challenge in Drosophila, we created a cell line that was more permissive to infection and detected novel viruses by the presence of double-stranded RNA. We demonstrate the utility of these tools by isolating La Jolla virus (LJV) and Newfield virus (NFV) from several wild Drosophila populations. These viruses have different potential host ranges, with distinct abilities to replicate in five Drosophila species. Similarly, in some species they cause high mortality and in others they are comparatively benign. In three species, NFV but not LJV caused large declines in female fecundity. This sterilization effect was associated with differences in tissue tropism, as NFV but not LJV was able to infect Drosophila melanogaster follicular epithelium and induce follicular degeneration in the ovary. We saw a similar effect in the invasive pest of fruit crops Drosophila suzukii, where oral infection with NFV caused reductions in the fecundity, suggesting it has potential as a biocontrol agent. In conclusion, a simple protocol allowed us to isolate new viruses and demonstrate that viruses identified by metagenomics have a large effect on the fitness of the model organism D. melanogaster and related species.
Assuntos
Drosophila , Vírus , Animais , Feminino , Drosophila melanogaster , InsetosRESUMO
When an animal is infected, the expression of a large suite of genes is changed, resulting in an immune response that can defend the host. Despite much evidence that the sequence of proteins in the immune system can evolve rapidly, the evolution of gene expression is comparatively poorly understood. We therefore investigated the transcriptional response to parasitoid wasp infection in Drosophila simulans and D. sechellia. Although these species are closely related, there has been a large scale divergence in the expression of immune-responsive genes in their two main immune tissues, the fat body and hemocytes. Many genes, including those encoding molecules that directly kill pathogens, have cis regulatory changes, frequently resulting in large differences in their expression in the two species. However, these changes in cis regulation overwhelmingly affected gene expression in immune-challenged and uninfected animals alike. Divergence in the response to infection was controlled in trans. We argue that altering trans-regulatory factors, such as signalling pathways or immune modulators, may allow natural selection to alter the expression of large numbers of immune-responsive genes in a coordinated fashion.
Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/genética , Evolução Molecular , Especificidade da Espécie , Proteínas de Drosophila/genética , ImunidadeRESUMO
Biological invasions are a major cause of environmental and economic disruption. While ecological factors are key determinants of their success, the role of genetics has been more challenging to demonstrate. The colonization of Australia by the European rabbit is one of the most iconic and devastating biological invasions in recorded history. Here, we show that despite numerous introductions over a 70-y period, this invasion was triggered by a single release of a few animals that spread thousands of kilometers across the continent. We found genetic support for historical accounts that these were English rabbits imported in 1859 by a settler named Thomas Austin and traced the origin of the invasive population back to his birthplace in England. We also find evidence of additional introductions that established local populations but have not spread geographically. Combining genomic and historical data we show that, contrary to the earlier introductions, which consisted mostly of domestic animals, the invasive rabbits had wild ancestry. In New Zealand and Tasmania, rabbits also became a pest several decades after being introduced. We argue that the common denominator of these invasions was the arrival of a new genotype that was better adapted to the natural environment. These findings demonstrate how the genetic composition of invasive individuals can determine the success of an introduction and provide a mechanism by which multiple introductions can be required for a biological invasion.
Assuntos
Animais Selvagens , Genética Populacional , Espécies Introduzidas , Coelhos , Animais , Animais Domésticos , Animais Selvagens/genética , Animais Selvagens/fisiologia , Austrália , Variação Genética , Genômica , Genótipo , História do Século XIX , História do Século XX , História do Século XXI , Espécies Introduzidas/estatística & dados numéricos , Nova Zelândia , Coelhos/genética , Coelhos/fisiologia , Tasmânia , Fatores de TempoRESUMO
Hosts are continually selected to evolve new defenses against an ever-changing array of pathogens. To understand this process, we examined the genetic basis of resistance to the Drosophila A virus in Drosophila melanogaster. In a natural population, we identified a polymorphic transposable element (TE) insertion that was associated with an â¼19,000-fold reduction in viral titers, allowing flies to largely escape the harmful effects of infection by this virulent pathogen. The insertion occurs in the protein-coding sequence of the gene Veneno, which encodes a Tudor domain protein. By mutating Veneno with CRISPR-Cas9 in flies and expressing it in cultured cells, we show that the ancestral allele of the gene has no effect on viral replication. Instead, the TE insertion is a gain-of-function mutation that creates a gene encoding a novel resistance factor. Viral titers remained reduced when we deleted the TE sequence from the transcript, indicating that resistance results from the TE truncating the Veneno protein. This is a novel mechanism of virus resistance and a new way by which TEs can contribute to adaptation.
Assuntos
Elementos de DNA Transponíveis , Dicistroviridae , Drosophila melanogaster , Interações Hospedeiro-Patógeno , Domínio Tudor , Animais , Elementos de DNA Transponíveis/genética , Drosophila melanogaster/genética , Drosophila melanogaster/virologia , Mutação com Ganho de Função , Interações Hospedeiro-Patógeno/genética , Deleção de SequênciaRESUMO
Wolbachia is a maternally transmitted bacterial symbiont that is estimated to infect approximately half of arthropod species. In the laboratory it can increase the resistance of insects to viral infection, but its effect on viruses in nature is unknown. Here we report that in a natural population of Drosophila melanogaster, individuals that are infected with Wolbachia are less likely to be infected by viruses. By characterising the virome by metagenomic sequencing and then testing individual flies for infection, we found the protective effect of Wolbachia was virus-specific, with the prevalence of infection being up to 15% greater in Wolbachia-free flies. The antiviral effects of Wolbachia may contribute to its extraordinary ecological success, and in nature the symbiont may be an important component of the antiviral defences of insects.
Assuntos
Drosophila melanogaster/microbiologia , Drosophila melanogaster/virologia , Wolbachia/fisiologia , Animais , Connecticut , Masculino , SimbioseRESUMO
The vinegar fly Drosophila melanogaster is a pivotal model for invertebrate development, genetics, physiology, neuroscience, and disease. The whole family Drosophilidae, which contains over 4,400 species, offers a plethora of cases for comparative and evolutionary studies. Despite a long history of phylogenetic inference, many relationships remain unresolved among the genera, subgenera, and species groups in the Drosophilidae. To clarify these relationships, we first developed a set of new genomic markers and assembled a multilocus data set of 17 genes from 704 species of Drosophilidae. We then inferred a species tree with highly supported groups for this family. Additionally, we were able to determine the phylogenetic position of some previously unplaced species. These results establish a new framework for investigating the evolution of traits in fruit flies, as well as valuable resources for systematics.
Assuntos
Drosophila melanogaster , Drosophila , Animais , Drosophila/genética , Drosophila melanogaster/genética , FilogeniaRESUMO
Organisms rely on inducible and constitutive immune defences to combat infection. Constitutive immunity enables a rapid response to infection but may carry a cost for uninfected individuals, leading to the prediction that it will be favoured when infection rates are high. When we exposed populations of Drosophila melanogaster to intense parasitism by the parasitoid wasp Leptopilina boulardi, they evolved resistance by developing a more reactive cellular immune response. Using single-cell RNA sequencing, we found that immune-inducible genes had become constitutively upregulated. This was the result of resistant larvae differentiating precursors of specialized immune cells called lamellocytes that were previously only produced after infection. Therefore, populations evolved resistance by genetically hard-wiring the first steps of an induced immune response to become constitutive.
Assuntos
Evolução Biológica , Resistência à Doença/imunologia , Drosophila melanogaster/imunologia , Imunidade Celular/imunologia , Infecções/imunologia , Animais , Resistência à Doença/genética , Drosophila melanogaster/parasitologia , Feminino , Regulação da Expressão Gênica , Hemócitos/imunologia , Larva/imunologia , Masculino , VespasRESUMO
It is common to find abundant genetic variation in host resistance and parasite infectivity within populations, with the outcome of infection frequently depending on genotype-specific interactions. Underlying these effects are complex immune defenses that are under the control of both host and parasite genes. We have found extensive variation in Drosophila melanogaster's immune response against the parasitoid wasp Leptopilina boulardi. Some aspects of the immune response, such as phenoloxidase activity, are predominantly affected by the host genotype. Some, such as upregulation of the complement-like protein Tep1, are controlled by the parasite genotype. Others, like the differentiation of immune cells called lamellocytes, depend on the specific combination of host and parasite genotypes. These observations illustrate how the outcome of infection depends on independent genetic effects on different aspects of host immunity. As parasite-killing results from the concerted action of different components of the immune response, these observations provide a physiological mechanism to generate phenomena like epistasis and genotype-interactions that underlie models of coevolution.
Assuntos
Drosophila melanogaster/imunologia , Drosophila melanogaster/parasitologia , Hemócitos/imunologia , Interações Hospedeiro-Parasita , Imunidade Humoral/imunologia , Vespas/imunologia , Animais , Drosophila melanogaster/genética , Feminino , Genótipo , Hemócitos/parasitologia , Masculino , Monofenol Mono-Oxigenase/metabolismo , Vespas/genética , Vespas/patogenicidadeRESUMO
Wolbachia, a common vertically transmitted symbiont, can protect insects against viral infection and prevent mosquitoes from transmitting viral pathogens. For this reason, Wolbachia-infected mosquitoes are being released to prevent the transmission of dengue and other arboviruses. An important question for the long-term success of these programmes is whether viruses can evolve to escape the antiviral effects of Wolbachia. We have found that Wolbachia altered the outcome of competition between strains of the DCV virus in Drosophila. However, Wolbachia still effectively blocked the virus genotypes that were favoured in the presence of the symbiont. We conclude that Wolbachia did cause an evolutionary response in viruses, but this has little or no impact on the effectiveness of virus blocking.
Assuntos
Drosophila/microbiologia , Simbiose , Vírus , Wolbachia/fisiologia , Aedes , Animais , Culicidae , Drosophila/fisiologia , VirosesRESUMO
Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Animais , Linhagem Celular , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Cães , Ativação Enzimática/efeitos dos fármacos , Humanos , Células Madin Darby de Rim Canino , Fosforilação , Doenças Renais Policísticas/metabolismo , Isoformas de ProteínasRESUMO
It is common to find considerable genetic variation in susceptibility to infection in natural populations. We have investigated whether natural selection increases this variation by testing whether host populations show more genetic variation in susceptibility to pathogens that they naturally encounter than novel pathogens. In a large cross-infection experiment involving four species of Drosophila and four host-specific viruses, we always found greater genetic variation in susceptibility to viruses that had coevolved with their host. We went on to examine the genetic architecture of resistance in one host species, finding that there are more major-effect genetic variants in coevolved host-pathogen interactions. We conclude that selection by pathogens has increased genetic variation in host susceptibility, and much of this effect is caused by the occurrence of major-effect resistance polymorphisms within populations.
Assuntos
Resistência à Doença/genética , Suscetibilidade a Doenças , Variação Genética , Interações Hospedeiro-Patógeno/genética , Infecções/genética , Alelos , Animais , Mapeamento Cromossômico , Drosophila melanogaster/genética , Feminino , Genes de Insetos , Infecções/virologia , Masculino , Polimorfismo Genético , Rhabdoviridae/fisiologia , Infecções por Rhabdoviridae/virologia , Seleção Genética , Especificidade da Espécie , Carga ViralRESUMO
Obesity is associated with an increased risk of depression. The aim of the present study was to investigate whether obesity is a causative factor for the development of depression and what is the molecular pathway(s) that link these two disorders. Using lipidomic and transcriptomic methods, we identified a mechanism that links exposure to a high-fat diet (HFD) in mice with alterations in hypothalamic function that lead to depression. Consumption of an HFD selectively induced accumulation of palmitic acid in the hypothalamus, suppressed the 3', 5'-cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and increased the concentration of free fatty acid receptor 1 (FFAR1). Deficiency of phosphodiesterase 4A (PDE4A), an enzyme that degrades cAMP and modulates stimulatory regulative G protein (Gs)-coupled G protein-coupled receptor signaling, protected animals either from genetic- or dietary-induced depression phenotype. These findings suggest that dietary intake of saturated fats disrupts hypothalamic functions by suppressing cAMP/PKA signaling through activation of PDE4A. FFAR1 inhibition and/or an increase of cAMP signaling in the hypothalamus could offer potential therapeutic targets to counteract the effects of dietary or genetically induced obesity on depression.
Assuntos
AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Depressão/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Hipotálamo/fisiopatologia , Obesidade/fisiopatologia , Animais , Comportamento Animal , Depressão/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Transdução de SinaisRESUMO
In the 1950s the myxoma virus was released into European rabbit populations in Australia and Europe, decimating populations and resulting in the rapid evolution of resistance. We investigated the genetic basis of resistance by comparing the exomes of rabbits collected before and after the pandemic. We found a strong pattern of parallel evolution, with selection on standing genetic variation favoring the same alleles in Australia, France, and the United Kingdom. Many of these changes occurred in immunity-related genes, supporting a polygenic basis of resistance. We experimentally validated the role of several genes in viral replication and showed that selection acting on an interferon protein has increased the protein's antiviral effect.
Assuntos
Adaptação Biológica/genética , Imunidade Inata/genética , Myxoma virus/imunologia , Mixomatose Infecciosa/imunologia , Coelhos/genética , Coelhos/virologia , Alelos , Animais , Austrália , Evolução Molecular , França , Frequência do Gene , Variação Genética , Interferon alfa-2/genética , Interferon alfa-2/imunologia , Mixomatose Infecciosa/genética , Polimorfismo de Nucleotídeo Único , População , Coelhos/imunologia , Reino UnidoRESUMO
Host shifts, where a pathogen invades and establishes in a new host species, are a major source of emerging infectious diseases. They frequently occur between related host species and often rely on the pathogen evolving adaptations that increase their fitness in the novel host species. To investigate genetic changes in novel hosts, we experimentally evolved replicate lineages of an RNA virus (Drosophila C Virus) in 19 different species of Drosophilidae and deep sequenced the viral genomes. We found a strong pattern of parallel evolution, where viral lineages from the same host were genetically more similar to each other than to lineages from other host species. When we compared viruses that had evolved in different host species, we found that parallel genetic changes were more likely to occur if the two host species were closely related. This suggests that when a virus adapts to one host it might also become better adapted to closely related host species. This may explain in part why host shifts tend to occur between related species, and may mean that when a new pathogen appears in a given species, closely related species may become vulnerable to the new disease.
Assuntos
Evolução Biológica , Drosophilidae/genética , Especificidade de Hospedeiro , Interações Hospedeiro-Patógeno , Filogenia , Vírus de RNA/genética , Fenômenos Fisiológicos Virais , Animais , Drosophilidae/classificação , Drosophilidae/virologia , Genoma Viral , Replicação ViralRESUMO
A priority for biomedical research is to understand the causes of variation in susceptibility to infection. To investigate genetic variation in a model system, we used flies collected from single populations of three different species of Drosophila and artificially selected them for resistance to the parasitoid wasp Leptopilina boulardi, and found that survival rates increased 3 to 30 fold within 6 generations. Resistance in all three species involves a large increase in the number of the circulating hemocytes that kill parasitoids. However, the different species achieve this in different ways, with D. melanogaster moving sessile hemocytes into circulation while the other species simply produce more cells. Therefore, the convergent evolution of the immune phenotype has different developmental bases. These changes are costly, as resistant populations of all three species had greatly reduced larval survival. In all three species resistance is only costly when food is in short supply, and resistance was rapidly lost from D. melanogaster populations when food is restricted. Furthermore, evolving resistance to L. boulardi resulted in cross-resistance against other parasitoids. Therefore, whether a population evolves resistance will depend on ecological conditions including food availability and the presence of different parasite species.
Assuntos
Evolução Biológica , Resistência à Doença/genética , Drosophila/imunologia , Drosophila/parasitologia , Vespas/patogenicidade , Animais , Resistência à Doença/imunologia , Drosophila/genética , Imunidade Celular/genética , Imunidade Celular/imunologia , Especificidade da Espécie , Vespas/imunologiaRESUMO
Wolbachia is a common heritable bacterial symbiont in insects. Its evolutionary success lies in the diverse phenotypic effects it has on its hosts coupled to its propensity to move between host species over evolutionary timescales. In a survey of natural host-symbiont associations in a range of Drosophila species, we found that 10 of 16 Wolbachia strains protected their hosts against viral infection. By moving Wolbachia strains between host species, we found that the symbiont genome had a much greater influence on the level of antiviral protection than the host genome. The reason for this was that the level of protection depended on the density of the symbiont in host tissues, and Wolbachia rather than the host-controlled density. The finding that virus resistance and symbiont density are largely under the control of symbiont genes in this system has important implications both for the evolution of these traits and for public health programmes using Wolbachia to prevent mosquitoes from transmitting disease.
Assuntos
Resistência à Doença , Drosophila/microbiologia , Simbiose , Wolbachia/genética , Animais , Drosophila/genética , Drosophila/virologia , Genoma Bacteriano , Genoma de Inseto , Fenótipo , Vírus/patogenicidadeRESUMO
BACKGROUND: The mosquito Aedes aegypti is the main vector of dengue, Zika, chikungunya and yellow fever viruses. This major disease vector is thought to have arisen when the African subspecies Ae. aegypti formosus evolved from being zoophilic and living in forest habitats into a form that specialises on humans and resides near human population centres. The resulting domestic subspecies, Ae. aegypti aegypti, is found throughout the tropics and largely blood-feeds on humans. RESULTS: To understand this transition, we have sequenced the exomes of mosquitoes collected from five populations from around the world. We found that Ae. aegypti specimens from an urban population in Senegal in West Africa were more closely related to populations in Mexico and Sri Lanka than they were to a nearby forest population. We estimate that the populations in Senegal and Mexico split just a few hundred years ago, and we found no evidence of Ae. aegypti aegypti mosquitoes migrating back to Africa from elsewhere in the tropics. The out-of-Africa migration was accompanied by a dramatic reduction in effective population size, resulting in a loss of genetic diversity and rare genetic variants. CONCLUSIONS: We conclude that a domestic population of Ae. aegypti in Senegal and domestic populations on other continents are more closely related to each other than to other African populations. This suggests that an ancestral population of Ae. aegypti evolved to become a human specialist in Africa, giving rise to the subspecies Ae. aegypti aegypti. The descendants of this population are still found in West Africa today, and the rest of the world was colonised when mosquitoes from this population migrated out of Africa. This is the first report of an African population of Ae. aegypti aegypti mosquitoes that is closely related to Asian and American populations. As the two subspecies differ in their ability to vector disease, their existence side by side in West Africa may have important implications for disease transmission.
Assuntos
Aedes/genética , Vetores de Doenças , Genômica , Adaptação Fisiológica/genética , África Ocidental , América , Migração Animal , Animais , Ásia , Sequência de Bases , Exoma/genética , Variação Genética , Genética Populacional , Genoma de Inseto , Humanos , Filogenia , Densidade Demográfica , Análise de Componente PrincipalRESUMO
A small number of free-living viruses have been found to be obligately vertically transmitted, but it remains uncertain how widespread vertically transmitted viruses are and how quickly they can spread through host populations. Recent metagenomic studies have found several insects to be infected with sigma viruses (Rhabdoviridae). Here, we report that sigma viruses that infect Mediterranean fruit flies (Ceratitis capitata), Drosophila immigrans, and speckled wood butterflies (Pararge aegeria) are all vertically transmitted. We find patterns of vertical transmission that are consistent with those seen in Drosophila sigma viruses, with high rates of maternal transmission, and lower rates of paternal transmission. This mode of transmission allows them to spread rapidly in populations, and using viral sequence data we found the viruses in D. immigrans and C. capitata had both recently swept through host populations. The viruses were common in nature, with mean prevalences of 12% in C. capitata, 38% in D. immigrans and 74% in P. aegeria We conclude that vertically transmitted rhabdoviruses may be widespread in a broad range of insect taxa, and that these viruses can have dynamic interactions with their hosts.