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Basic science holds enormous power for revealing the biological mechanisms of disease and, in turn, paving the way toward new, effective interventions. Recognizing this power, the 2011 Research Agenda for Malaria Eradication included key priorities in fundamental research that, if attained, could help accelerate progress toward disease elimination and eradication. The Malaria Eradication Research Agenda (malERA) Consultative Panel on Basic Science and Enabling Technologies reviewed the progress, continuing challenges, and major opportunities for future research. The recommendations come from a literature of published and unpublished materials and the deliberations of the malERA Refresh Consultative Panel. These areas span multiple aspects of the Plasmodium life cycle in both the human host and the Anopheles vector and include critical, unanswered questions about parasite transmission, human infection in the liver, asexual-stage biology, and malaria persistence. We believe an integrated approach encompassing human immunology, parasitology, and entomology, and harnessing new and emerging biomedical technologies offers the best path toward addressing these questions and, ultimately, lowering the worldwide burden of malaria., Dyann F. Wirth and colleagues propose a research agenda for basic science and enabling technologies in malaria elimination and eradication.

Discovering the molecular factors that shape the mating behaviour and the fertility of the mosquito Anopheles gambiae, the principal vector of human malaria, is regarded as critical to better understand its reproductive success as well as for identifying new leads for malaria control measures. In A. gambiae mating induces complex behavioural and physiological changes in the females, including refractoriness to subsequent mating and induction of egg-laying. In other insects including Drosophila a group of proteins named Accessory gland proteins (Acps), produced by males and transferred with sperm to the female reproductive tract, have been implicated in this post-mating response. Although Acps represent a set of promising candidates for unravelling the mating physiology, their role in inducing behavioural changes in mated A. gambiae females remains largely unknown. In this work, we demonstrate that a down-regulation of a large fraction of Acp genes via silencing of the Acp regulating transcription factor Hsf, abolishes the formation of mating plug in mated females and fails to induce refractoriness of mated female to subsequent inseminations. A significant fraction of females mated to Hsf silenced males (66%) failed to receive the mating plug though seminal fluid had been transferred as documented by the presence of spermatozoa in the female sperm storage organ. Furthermore, nearly all females (95%) mated to HSF-silenced males were re-inseminated when exposed to males carrying EGPF marked sperm. Our findings provide evidence showing that Acp genes regulated by the transcription factor HSF play a key role in the function of the male accessory glands.

Malaria continues to place a disease burden on millions of people throughout the tropics, especially in sub-Saharan Africa. Although efforts to control mosquito populations and reduce human-vector contact, such as long-lasting insecticidal nets and indoor residual spraying, have led to significant decreases in malaria incidence, further progress is now threatened by the widespread development of physiological and behavioural insecticide-resistance as well as changes in the composition of vector populations. A mosquito-directed push-pull system based on the simultaneous use of attractive and repellent volatiles offers a complementary tool to existing vector-control methods. In this study, the combination of a trap baited with a five-compound attractant and a strip of net-fabric impregnated with micro-encapsulated repellent and placed in the eaves of houses, was tested in a malaria-endemic village in western Kenya. Using the repellent delta-undecalactone, mosquito house entry was reduced by more than 50%, while the traps caught high numbers of outdoor flying mosquitoes. Model simulations predict that, assuming area-wide coverage, the addition of such a push-pull system to existing prevention efforts will result in up to 20-fold reductions in the entomological inoculation rate. Reductions of such magnitude are also predicted when mosquitoes exhibit a high resistance against insecticides. We conclude that a push-pull system based on non-toxic volatiles provides an important addition to existing strategies for malaria prevention.

International audience; To better understand the olfactory mechanisms in a lepidopteran pest model species, the cotton leafworm Spodoptera littoralis, we have recently established a partial transcriptome from adult antennae. Here, we completed this transcriptome using next generation sequencing technologies, namely 454 and Illumina, on both adult antennae and larval tissues, including caterpillar antennae and maxillary palps. All sequences were assembled in 77,643 contigs. Their analysis greatly enriched the repertoire of chemosensory genes in this species, with a total of 57 candidate odorant-binding and chemosensory proteins, 47 olfactory receptors, 6 gustatory receptors and 17 ionotropic receptors. Using RT-PCR, we conducted the first exhaustive comparison of olfactory gene expression between larvae and adults in a lepidopteran species. All the 127 candidate olfactory genes were profiled for expression in male and female adult antennae and in caterpillar antennae and maxillary palps. We found that caterpillars expressed a smaller set of olfactory genes than adults, with a large overlap between these two developmental stages. Two binding proteins appeared to be larvae-specific and two others were adult-specific. Interestingly, comparison between caterpillar antennae and maxillary palps revealed numerous organ-specific transcripts, suggesting the complementary involvement of these two organs in larval chemosensory detection. Adult males and females shared the same set of olfactory transcripts, except two male-specific candidate pheromone receptors, two male-specific and two female-specific odorant-binding proteins. This study identified transcripts that may be important for sex-specific or developmental stage-specific chemosensory behaviors.

author can archive publisher's version/PDF (embargo 6 months) ; 1529-2401 (Electronic ISSN); International audience; To sense myriad environmental odors, animals have evolved multiple, large families of divergent olfactory receptors. How and why distinct receptor repertoires and their associated circuits are functionally and anatomically integrated is essentially unknown. We have addressed these questions through comprehensive comparative analysis of the Drosophila olfactory subsystems that express the ionotropic receptors (IRs) and odorant receptors (ORs). We identify ligands for most IR neuron classes, revealing their specificity for select amines and acids, which complements the broader tuning of ORs for esters and alcohols. IR and OR sensory neurons exhibit glomerular convergence in segregated, although interconnected, zones of the primary olfactory center, but these circuits are extensively interdigitated in higher brain regions. Consistently, behavioral responses to odors arise from an interplay between IR- and OR-dependent pathways. We integrate knowledge on the different phylogenetic and developmental properties of these receptors and circuits to propose models for the functional contributions and evolution of these distinct olfactory subsystems.

Anopheles gambiae sensu stricto and Aedes aegypti have a preference for human blood, which determines their importance as vectors of pathogens responsible for human diseases. Volatile organic chemicals are the principal cues by which humans are being located. Human sweat contains components that are attractive to anthropophilic mosquito species, and variation in sweat composition causes differential attractiveness to mosquitoes within and between individuals and also between humans and other mammals. Characteristics of skin glands and skin microbiota define the odorous organic compounds emitted by sweat, thereby the degree of attractiveness of the host to mosquitoes. Carboxylic acids in particular appear to characterize humans. Thus sweat-associated human volatiles are probably the primary determinant factor in the host preference of anthropophilic mosquitoes.

Historical Profiles and Perspectives From Tucson to Genomics and Transgenics: The Vector Biology Network and the Emergence of Modern Vector Biology Barry J. Beaty 1 *, Denis J. Prager 2 , Anthony A. James 3,4 , Marcelo Jacobs-Lorena 5 , Louis H. Miller 6 , John H. Law 7,8,9 , Frank H. Collins 1 , Fotis C. Kafatos 1 1 Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America, 2 Strategic Consulting Services, Clyde Park, Montana, United States of America, 3 Department of Microbiology & Molecular Genetics, University of California Irvine, Irvine, California, United States of America, 4 Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, California, United States of America, 5 Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America, 6 Malaria Vaccine Development Branch, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America, 7 Department of Biochemistry and Molecular Biophysics, University of Arizona Tucson, Tucson, Arizona, United States of America, 8 Department of Entomology, University of Arizona Tucson, Tucson, Arizona, United States of America, 9 Department of Entomology, University of Georgia, Athens, Georgia, United States of America, 10 Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America, 11 Faculty of Natural Sciences, Imperial College London, London, United Kingdom Introduction The research enterprise is often charged with responding to emerging scientific needs and opportunities involving impor- tant public health issues. The establish- ment of the Vector Biology Network (VBN) by The MacArthur Foundation to address critical scientific, research, and human resource needs in vector biology is a model of how to respond to such a charge efficiently and effectively. When the Network was formed in 1989, the resurgence of vector-borne diseases, in- cluding malaria and dengue, had revealed critical research and training needs in vector biology. Major knowledge gaps in vector molecular biology and pathogen transmission limited development of new approaches for vector and disease control. The loss of vector biologists/medical entomologists complicated control of these diseases. Members of the VBN, an inter- national consortium of research laborato- ries, collaborated in the development and application of modern molecular and genetic approaches in vector biology and in the training of a new cadre of scientists capable of developing and applying mod- ern tools to combat these diseases. The VBN exploited the expertise and resources of the consortium institutions, and exceed- ed all of its milestones, including: devel- opment of molecular and genomic ap- proaches in vector biology; genetic transformation of insect vectors; charac- terization of vector immune systems; identification of molecular and biological bases of vector competence; and exploita- tion of identified vulnerabilities to interfere with pathogen transmission. The VBN recruited many established scientists from other fields and trained a new generation www.plosntds.org of leaders in vector biology. Most impor- tantly, the VBN participated in and helped catalyze a remarkable renaissance in vector biology/medical entomology. A Case Study of Collaborative Development of a Research Field Research on mosquitoes and other arthropod vectors of infectious diseases is of great importance for tackling neglected tropical diseases in the developing world. Vector biology is now a well-established and rapidly advancing field that is provid- ing new understanding of vectors and vector pathogen interactions and creating new opportunities for vector-borne disease (VBD) control. Many key milestones and recruitment and training of new research- ers in this field were made possible by the coalescence of several laboratories in the US and Europe into a collaborative research network focused on the biology of disease vectors. The Vector Biology Network (VBN) was established and fund- ed for ten years (1990–2000) by The John D. and Catherine T. MacArthur Founda- tion. The VBN was reinforced through endorsement and, in some cases, coordi- nated funding by the World Health Organization (WHO) and national re- search agencies and foundations, which collectively contributed to a remarkable renaissance of vector biology. The history of the VBN provides a valuable case study of how effective strategies can be devel- oped and deployed to address cost-effec- tively newly recognized scientific challeng- es related to important public health and social goals. The Challenge: Resurgence of Vector-Borne Diseases The stimulus for developing the VBN was the worldwide resurgence of VBDs. While extraordinary advances in antibiot- ics and vaccines have controlled many infectious diseases, VBDs continue to afflict hundreds of millions of humans annually, resulting in inestimable morbid- ity and misery and millions of deaths in disease-endemic countries [1]. These dis- eases are resurging in areas where they were previously controlled and are newly Citation: Beaty BJ, Prager DJ, James AA, Jacobs-Lorena M, Miller LH, et al. (2009) From Tucson to Genomics and Transgenics: The Vector Biology Network and the Emergence of Modern Vector Biology. PLoS Negl Trop Dis 3(3): doi:10.1371/journal.pntd.0000343 Editor: Serap Aksoy, Yale University School of Medicine, United States of America Published March 31, 2009 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: This work was supported by The MacArthur Foundation. Competing Interests: All authors were members of The MacArthur Foundation Network on the Biology of Parasite Vectors (VBN), and all contributed to the preparation of this publication. Dr. Prager was the Director of Health Programs at the Foundation during the time of the VBN. None of the authors are currently funded by the Foundation. * E-mail: bbeaty@colostate.edu March 2009 | Volume 3 | Issue 3 | e343

The ookinete surface proteins (P25 and P28) are proven antimalarial transmission-blocking vaccine targets, yet their biological functions are unknown. By using single (Sko) and double gene knock-out (Dko) Plasmodium berghei parasites, we show that P25 and P28 share multiple functions during ookinete/oocyst development. In the midgut of mosquitoes, the formation of ookinetes lacking both proteins (Dko parasites) is significantly inhibited due to decreased protection against lethal factors, including protease attack. In addition, Dko ookinetes have a much reduced capacity to traverse the midgut epithelium and to transform into the oocyst stage. P25 and P28 are partially redundant in these functions, since the efficiency of ookinete/oocyst development is only mildly compromised in parasites lacking either P25 or P28 (Sko parasites) compared with that of Dko parasites. The fact that Sko parasites are efficiently transmitted by the mosquito is a compelling reason for including both target antigens in transmission-blocking vaccines.

The last few years have witnessed a considerable expansion in the number of tools available to perform molecular and genetic studies on the genome of Anopheles mosquitoes, the vectors of human malaria. As a consequence, knowledge of aspects of the biology of mosquitoes, such as immunity, reproduction and behaviour, that are relevant to their ability to transmit disease is rapidly increasing, and could be translated into concrete benefits for malaria control strategies. Amongst the most important scientific advances, the development of transgenic technologies for Anopheles mosquitoes provides a crucial opportunity to improve current vector control measures or design novel ones. In particular, the use of genetic modification of the mosquito genome could provide for a more effective deployment of the sterile insect technique (SIT) against vector populations in the field. Currently, SIT relies on the release of radiation sterilized males, which compete with wild males for mating with wild females. The induction of sterility in males through the genetic manipulation of the mosquito genome, already achieved in a number of other insect species, could eliminate the need for radiation and increase the efficiency of SIT-based strategies. This paper provides an overview of the mechanisms already in use for inducing sterility by transgenesis in Drosophila and other insects, and speculates on possible ways to apply similar approaches to Anopheles mosquitoes.

The detection of odour stimuli in the environment is universally important for primal behaviours such as feeding, mating, kin interactions and escape responses. Given the ubiquity of many airborne chemical signals and the similar organisation of animal olfactory circuits, a fundamental question in our understanding of the sense of smell is how species-specific behavioural responses to odorants can evolve. Recent comparative genomic, developmental and physiological studies are shedding light on this problem by providing insights into the genetic mechanisms that underlie anatomical and functional evolution of the olfactory system. Here we synthesise these data, with a particular focus on insect olfaction, to address how new olfactory receptors and circuits might arise and diverge, offering glimpses into how odour-evoked behaviours could adapt to an ever-changing chemosensory world.

Background Mosquito eggshells show remarkable diversity in physical properties and structure consistent with adaptations to the wide variety of environments exploited by these insects. We applied proteomic, transcriptomic, and hybridization in situ techniques to identify gene products and pathways that participate in the assembly of the Aedes aegypti eggshell. Aedes aegypti population density is low during cold and dry seasons and increases immediately after rainfall. The survival of embryos through unfavorable periods is a key factor in the persistence of their populations. The work described here supports integrated vector control approaches that target eggshell formation and result in Ae. aegypti drought-intolerant phenotypes for public health initiatives directed to reduce mosquito-borne diseases. Results A total of 130 proteins were identified from the combined mass spectrometric analyses of eggshell preparations. Conclusions Classification of proteins according to their known and putative functions revealed the complexity of the eggshell structure. Three novel Ae. aegypti vitelline membrane proteins were discovered. Odorant-binding and cysteine-rich proteins that may be structural components of the eggshell were identified. Enzymes with peroxidase, laccase and phenoloxidase activities also were identified, and their likely involvements in cross-linking reactions that stabilize the eggshell structure are discussed.