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Tsetse flies are the sole vectors of human African trypanosomiasis throughout sub-Saharan Africa. Both sexes of adult tsetse feed exclusively on blood and contribute to disease transmission. Notable differences between tsetse and other disease vectors include obligate microbial symbioses, viviparous reproduction, and lactation. Here, we describe the sequence and annotation of the 366-megabase Glossina morsitans morsitans genome. Analysis of the genome and the 12,308 predicted protein–encoding genes led to multiple discoveries, including chromosomal integrations of bacterial (Wolbachia) genome sequences, a family of lactation-specific proteins, reduced complement of host pathogen recognition proteins, and reduced olfaction/chemosensory associated genes. These genome data provide a foundation for research into trypanosomiasis prevention and yield important insights with broad implications for multiple aspects of tsetse biology.

Cytoplasmic Incompatibility (CI) causes embryonic lethality in arthropods, resulting in a significant reduction in reproductive success. In most cases, this reproductive failure is driven by Wolbachia endosymbionts through their cifA - cifB gene pair, whose products disrupts arthropod DNA replication during embryogenesis. While a cif pair has been considered a hallmark of Wolbachia , its presence and functional significance in other bacterial lineages remains poorly investigated. Here, we conducted a comprehensive survey of 762 genomes spanning non- Wolbachia endosymbionts and their close relatives, revealing that the cif pair is far more widespread than previously recognized. We identified cif loci in 8.4% of the surveyed genomes, with a striking incidence of 17.4% in facultative symbionts. Beyond Wolbachia , cif pair occurs across eight bacterial genera spanning α-Proteobacteria, γ-Proteobacteria, Mollicutes, and Bacteroidota. Notably, cif pair has been identified in several intracellular pathogens of mammals showing high rate of transovarial transmission in their arthropod hosts, suggesting a potential role of cif pair and CI in vector-borne disease dynamics. Structural analyses further reveal that the PD(D/E)-XK nucleases and AAA-ATPase-like motifs are consistently conserved across cif pairs in all bacterial taxa. Moreover, cif pairs are frequently integrated within diverse mobile genetic elements, from transposons to large intact WO prophages in Wolbachia and RAGEs in Rickettsiaceae. Phylogenetic analyses reveal recent and potentially ongoing horizontal transfers of cif pair between distantly related bacterial lineages, a process potentially facilitated by mobile genetic elements. Indeed, the PDDEXK2 transposase exhibits a phylogenetic pattern consistent with the co-transmission of cif genes, suggesting that it may facilitate horizontal transfers of cif across bacterial lineages. Furthermore, the detection of endosymbionts harboring cif pair in arthropod groups where Wolbachia is scarce, such as ticks, suggests that CI may be more widespread than previously known, with significant implications for arthropod symbiosis, reproductive manipulation, and future biocontrol strategies.

Important arboviral diseases, such as dengue, chikungunya, and Zika virus infections, are transmitted mainly by the Aedes aegypti vector. So far, controlling this vector species with current tools and strategies has not demonstrated sustainable and significant impacts. Our main objective was to evaluate whether open field release of sterile males, produced from combining the sterile insect technique using radiation with the insect incompatible technique through Wolbachia-induced incompatibility (SIT/IIT), could suppress natural populations of Ae. aegypti in semi-rural village settings in Thailand. Irradiated Wolbachia-infected Aedes aegypti males produced by the SIT/IIT approach were completely sterile and were able to compete with the wild fertile ones. Open field release of these sterile males was conducted in an ecologically isolated village in Chachoengsao Province, eastern Thailand. House-to-house visit and media reports resulted in community acceptance and public awareness of the technology. During intervention, approximately 100-200 sterile males were released weekly in each household. After 6 months of sterile male release, a significant reduction (p<0.05) of the mean egg hatch rate (84%) and the mean number of females per household (97.30%) was achieved in the treatment areas when compared to the control ones. Our study represents the first open field release of sterile Ae. aegypti males developed from a combined SIT/IIT approach. Entomological assessment using ovitraps, adult sticky traps, and portable vacuum aspirators confirmed the success in reducing natural populations of Ae. aegypti females in treated areas. Public awareness through media resulted in positive support for practical use of this strategy in wider areas. Further study using a systematic randomized trial is needed to determine whether this approach could have a significant impact on the diseases transmitted by Ae. aegypti vector.

Abstract Wolbachia are endosymbiotic bacteria inducing various reproductive manipulations of which cytoplasmic incompatibility is the most common. Cytoplasmic incompatibility leads to reduced embryo viability in crosses between males carrying Wolbachia and uninfected females or those carrying an incompatible symbiont strain. In the mosquito Culex pipiens, the Wolbachia wPip causes highly complex crossing patterns. This complexity is linked to the amplification and diversification of the cytoplasmic incompatibility causal genes, cidA and cidB, with polymorphism located in the CidA–CidB interaction regions. We previously showed that some compatibility patterns correlated with the presence or absence of specific cid variants. It is still unknown, however, whether cid gene polymorphism alone is sufficient to explain the diversity of crossing patterns observed in Cx. pipiens. Taking advantage of a new method enabling full-gene acquisition, we sequenced complete cid repertoires from 45 wPip strains collected worldwide. We demonstrated that the extensive diversity of cid genes arises from recombination and horizontal transfers. We uncovered further cidB polymorphism located outside the interface regions and strongly correlated with cytoplasmic incompatibility patterns. Most importantly, we showed that in every wPip genome, all but one cidB variant are truncated. Truncated cidBs located in palindromes are partially or completely deprived of their deubiquitinase domain, crucial for cytoplasmic incompatibility. The identity of the sole full-length cidB variant seems to dictate cytoplasmic incompatibility patterns, irrespective of the truncated cidBs present. Truncated CidBs exhibit reduced toxicity and stability in Drosophila cells, which potentially hinders their loading into sperm, essential for cytoplasmic incompatibility induction.

Dengue exhibits focal clustering in households and neighborhoods, driven by local mosquito population dynamics, human population immunity, and fine scale human and mosquito movement. We tested the hypothesis that spatiotemporal clustering of homotypic dengue cases is disrupted by introduction of the arbovirus-blocking bacterium Wolbachia ( w Mel-strain) into the Aedes aegypti mosquito population. We analysed 318 serotyped and geolocated dengue cases (and 5921 test-negative controls) from a randomized controlled trial in Yogyakarta, Indonesia of w Mel deployments. We find evidence of spatial clustering up to 300 m among the 265 dengue cases (3083 controls) in the untreated trial arm. Participant pairs enrolled within 30 days and 50 m had a 4.7-fold increase (compared to 95% CI on permutation-based null distribution: 0.1, 1.2) in the odds of being homotypic (i.e. potentially transmission-related) as compared to pairs occurring at any distance. In contrast, we find no evidence of spatiotemporal clustering among the 53 dengue cases (2838 controls) resident in the w Mel-treated arm. Introgression of w Mel Wolbachia into Aedes aegypti mosquito populations interrupts focal dengue virus transmission leading to reduced case incidence; the true intervention effect may be greater than the 77% efficacy measured in the primary analysis of the Yogyakarta trial.

The discovery of two genes encoded by prophage WO from Wolbachia that functionally recapitulate and enhance cytoplasmic incompatibility in arthropods is the first inroad in solving the genetic basis of reproductive parasitism. Manipulation of insect survival by Wolbachia bacteria Bacteria from the genus Wolbachia infect many arthropods, including the mosquitoes that are vectors for many viruses that infect humans. Wolbachia infection causes 'cytoplasmic incompatibility', which means that crosses between infected males and uninfected females lead to embryonic death, increasing the proportion of infected females in the population. The molecular basis for this effect has been unknown. Here, Seth Bordenstein and colleagues use comparative and transgenic approaches to identify two genes encoded by the prophage WO from Wolbachia that recapitulate cytoplasmic incompatibility. The discovery of these cytoplasmic incompatibility factors could lead to the genetic manipulation of WO-induced reproductive alterations, and may feed into efforts to control the transmission of arthropod-borne viruses to humans. The genus Wolbachia is an archetype of maternally inherited intracellular bacteria that infect the germline of numerous invertebrate species worldwide. They can selfishly alter arthropod sex ratios and reproductive strategies to increase the proportion of the infected matriline in the population. The most common reproductive manipulation is cytoplasmic incompatibility, which results in embryonic lethality in crosses between infected males and uninfected females. Females infected with the same Wolbachia strain rescue this lethality. Despite more than 40 years of research 1 and relevance to symbiont-induced speciation 2 , 3 , as well as control of arbovirus vectors 4 , 5 , 6 and agricultural pests 7 , the bacterial genes underlying cytoplasmic incompatibility remain unknown. Here we use comparative and transgenic approaches to demonstrate that two differentially transcribed, co-diverging genes in the eukaryotic association module of prophage WO 8 from Wolbachia strain w Mel recapitulate and enhance cytoplasmic incompatibility. Dual expression in transgenic, uninfected males of Drosophila melanogaster crossed to uninfected females causes embryonic lethality. Each gene additively augments embryonic lethality in crosses between infected males and uninfected females. Lethality associates with embryonic defects that parallel those of wild-type cytoplasmic incompatibility and is notably rescued by w Mel-infected embryos in all cases. The discovery of cytoplasmic incompatibility factor genes cifA and cifB pioneers genetic studies of prophage WO-induced reproductive manipulations and informs the continuing use of Wolbachia to control dengue and Zika virus transmission to humans.

Animal hosts have initiated myriad symbiotic associations with microorganisms and often have maintained these symbioses for millions of years, spanning drastic changes in ecological conditions and lifestyles. The establishment and persistence of these relationships require genetic innovations on the parts of both symbionts and hosts. The nature of symbiont innovations depends on their genetic population structure, categorized here as open, closed or mixed. These categories reflect modes of inter-host transmission that result in distinct genomic features, or genomic syndromes, in symbionts. Although less studied, hosts also innovate in order to preserve and control symbiotic partnerships. New capabilities to sequence host-associated microbial communities and to experimentally manipulate both hosts and symbionts are providing unprecedented insights into how genetic innovations arise under different symbiont population structures and how these innovations function to support symbiotic relationships.The evolutionary persistence of animal symbioses depends on both host and symbiont innovations. Perreau and Moran review how genome sequencing and related experiments have clarified how these innovations arise under different symbiont population structures, categorized here as open, closed and mixed.

Wolbachia are maternally inherited bacteria that infect arthropod species worldwide and are deployed in vector control to curb arboviral spread using cytoplasmic incompatibility (CI). CI kills embryos when an infected male mates with an uninfected female, but the lethality is rescued if the female and her embryos are likewise infected. Two phage WO genes, cifAwMel and cifBwMel from the wMel Wolbachia deployed in vector control, transgenically recapitulate variably penetrant CI, and one of the same genes, cifAwMel, rescues wild type CI. The proposed Two-by-One genetic model predicts that CI and rescue can be recapitulated by transgenic expression alone and that dual cifAwMel and cifBwMel expression can recapitulate strong CI. Here, we use hatch rate and gene expression analyses in transgenic Drosophila melanogaster to demonstrate that CI and rescue can be synthetically recapitulated in full, and strong, transgenic CI comparable to wild type CI is achievable. These data explicitly validate the Two-by-One model in wMel-infected D. melanogaster, establish a robust system for transgenic studies of CI in a model system, and represent the first case of completely engineering male and female animal reproduction to depend upon bacteriophage gene products.

Endosymbiotic bacteria living in plasmodia or worm parasites are required for the homoeostasis of their host and should be excellent targets for chemotherapy of certain parasitic diseases. We show that targeting of Wolbachia spp bacteria in Onchocerca volvulus filariae by doxycycline leads to sterility of adult worms to an extent not seen with drugs used against onchocerciasis, a leading cause of blindness in African countries.

Wolbachia are successful Gram-negative bacterial endosymbionts, globally infecting a large fraction of arthropod species and filarial nematodes. Efficient vertical transmission, the capacity for horizontal transmission, manipulation of host reproduction and enhancement of host fitness can promote the spread both within and between species. Wolbachia are abundant and can occupy extraordinary diverse and evolutionary distant host species, suggesting that they have evolved to engage and manipulate highly conserved core cellular processes. Here, we review recent studies identifying Wolbachia–host interactions at the molecular and cellular levels. We explore how Wolbachia interact with a wide array of host cytoplasmic and nuclear components in order to thrive in a diversity of cell types and cellular environments. This endosymbiont has also evolved the ability to precisely target and manipulate specific phases of the host cell cycle. The remarkable diversity of cellular interactions distinguishes Wolbachia from other endosymbionts and is largely responsible for facilitating its global propagation through host populations. Finally, we describe how insights into Wolbachia–host cellular interactions have led to promising applications in controlling insect-borne and filarial nematode-based diseases.In this Review, Porter and Sullivan examine how Wolbachia interact with diverse host cellular components driving the endosymbiont’s global spread and discuss strategies to exploit Wolbachia for insect-based and parasite-based disease control.