Leslie B Vosshall’s research while affiliated with Rockefeller University and other places

What is this page?


This page lists works of an author who doesn't have a ResearchGate profile or hasn't added the works to their profile yet. It is automatically generated from public (personal) data to further our legitimate goal of comprehensive and accurate scientific recordkeeping. If you are this author and want this page removed, please let us know.

Publications (182)


Figure 3: Comparison of genital interactions and behaviors in Aedes albopictus and Aedes aegypti a. Distribution maps of detection events of Aedes aegypti and Aedes albopictus mosquitoes in 1915-1980 and 1981-2023. b. Scanning electron microscopy images of the ventral side of Aedes aegypti and Aedes albopictus male genitals. Gonostyli are pseudo-colored orange (Aedes aegypti) and turquoise (Aedes albopictus) c. Experimental setup for recording of genital behavior of a pin-tethered female and free-flying males. d-f. Representative video still image of the tips of the male and female during the three major steps towards successful mating in Aedes albopictus mosquitoes and number of events per 5 minutes of video recordings of (d) male genital contact, (e) female genital tip elongation, and (f) genital interlocking -in virgin and previously mated female video recordings. N=12 video recordings with 1 female and 5 males per condition. Time stamp represents time since the depicted video still image of male genital contact. Median (thick dotted black line) and
Mosquito sex under lock and key
  • Preprint
  • File available

April 2025

·

5 Reads

·

Madison M. Walker

·

Jacopo Razzauti

·

[...]

·

Leslie B. Vosshall

Female mosquitoes typically mate once in a lifetime 1–3 , making this singular mating decision critically important for the female. Yet, mosquito mating has been historically viewed as male-guided, with the female exerting little control 4–6 . To understand this contradiction, we investigated initiation of successful mating in mosquitoes. Here we show that females of two invasive mosquito species, the yellow fever mosquito ( Aedes aegypti ) and the Asian tiger mosquito ( Aedes albopictus ), actively gate mating through a previously undescribed behavior of female genital tip elongation. This female genital response is triggered by a rapidly-evolving secondary male genital structure that together act as a “lock-and-key” mechanism. We identified important differences in the genital interactions of the two species and show that Aedes albopictus males, which have larger secondary male genital structures, can bypass the female genital response of Aedes aegypti females but not of females of their own species. Coupled with previous observations that Aedes aegypti females are effectively sterilized by such cross-species mating 7–9 , the ability of male Aedes albopictus to “pick the lock” of heterospecific females provides a potential mechanism for the observed local extinction of Aedes aegypti when they live in shared territory with Aedes albopictus 10,11 . Our results redefine mosquito mating as a female-controlled process, with implications for the evolution of reproductive barriers and the population dynamics of these two globally invasive mosquito species.

Download

Mosquito Cell Atlas: A single-nucleus transcriptomic atlas of the adult Aedes aegypti mosquito

February 2025

·

91 Reads

·

2 Citations

The female mosquito’s remarkable ability to hunt humans and transmit pathogens relies on her unique biology. Here, we present the Mosquito Cell Atlas (MCA), a comprehensive single-nucleus RNA sequencing dataset of more than 367,000 nuclei from 19 dissected tissues of adult female and male Aedes aegypti , providing cellular-level resolution of mosquito biology. We identify novel cell types and expand our understanding of sensory neuron organization of chemoreceptors to all sensory tissues. Our analysis uncovers male-specific cells and sexually dimorphic gene expression in the antenna and brain. In female mosquitoes, we find that glial cells in the brain, rather than neurons, undergo the most extensive transcriptional changes following blood feeding. Our findings provide insights into the cellular basis of mosquito behavior and sexual dimorphism. The MCA aims to serve as a resource for the vector biology community, enabling systematic investigation of cell-type specific expression across all mosquito tissues.


Cross-modal sensory compensation increases mosquito attraction to humans

January 2025

·

27 Reads

·

5 Citations

Science Advances

Sensory compensation occurs when loss of one sense leads to enhanced perception by another sense. We have identified a previously undescribed mechanism of sensory compensation in female Aedes aegypti mosquitoes. Odorant receptor co-receptor ( Orco ) mutants show enhanced attraction to human skin temperature and increased heat-evoked neuronal activity in foreleg sensory neurons. Ir140 , a foreleg-enriched member of the ionotropic receptor (IR) superfamily of sensory receptors, is up-regulated in Orco mutant legs. Ir140 , Orco double mutants do not show the enhanced heat seeking seen in Orco single mutants, suggesting that up-regulation of Ir140 in the foreleg is a key mechanism underlying sensory compensation in Orco mutants. Because Orco expression is sparse in legs, this sensory compensation requires an indirect, long-range mechanism. Our findings highlight how female Aedes aegypti mosquitoes, despite suffering olfactory sensory loss, maintain the overall effectiveness of their host-seeking behavior by up-regulating attraction to human skin temperature, further enhancing their status as the most dangerous predator of humans.


Structure-guided design to synthesize novel NPYLR7 agonists. A Representation of Ae. aegypti host-seeking behavior by feeding status. B NPYLR7-predicted structure model with compound TDI-012631 bound (left) and predicted side-chain interactions (right). C Representative 384-well plate layout from in vitro screen displaying raw fluorescence units (RFU) corresponding to test compounds ranging from concentration of 100 to 0 μM from left to right. Negative control (column 1) is measured as response to assay buffer alone, and positive control (column 24) as response to 10 μM dose of FMRFa3, an endogenous peptide activator of NPYLR7. D Semilogarithmic curves of compound TDI-012615 (EC50 = 1.62 μM, black line) and FMRFa3 (peptide control) sigmoidal curve (EC50 = 4.11 μM, gray line). E Outline of in vitro screening for 128 newly synthesized NPYLR7 agonists binned according to in vitro EC50
Small-molecule NPYLR7 agonists tested in vivo. A Lead compound scaffold with conserved quinazoline core, guanidine group, and R groups tested for substitutions. Shading in legend indicates EC50 in B. B Chemical structures with corresponding in vitro EC50 of each compound tested in behavioral assays arranged with the highest value at the top left to the lowest value at the bottom right. TDI-012631 (center, black border) is the initial reference compound
Miniport olfactometer screening assay to identify compounds that reduce attraction to human host cues. A Schematic of the miniport olfactometer host-seeking assay. Inset depicts start canister and attraction trap modular components for each experiment. Mosquitoes not drawn to scale. B Host-seeking relative to saline (test compound % host-seeking/average matched saline % host-seeking). (Median with interquartile range, n = 4–65 replicates, 15–20 females/replicate) C Correlation of in vitro potency to in vivo host-seeking in Ae. aegypti. Spearman correlation coefficient (ρ) = 0.1374, P > 0.05, slope = 0.002942, R² = 0.01525
Novel NPYLR7 agonists reduce blood-feeding from a live host when fed at a dose of 1 μM. A Schematic of “mouse-in-cage” biting assay workflow depicting powder color assignment, exposure to mouse, and scoring of fresh blood in the abdomen. B–F Percentage of females that freshly blood-fed on an anesthetized mouse after 15 min exposure. Females were fed the indicated meal 48 h prior to the experiment. C, D, F High-potency and (E) medium-potency in vitro compounds (see Fig. 2B). Bold lines represent saline group mean versus test group mean. Total of 15–20 females per replicate. Mann–Whitney test: Bn = 13 replicates, ***P = 0.0003; Cn = 9 replicates; ns, not significant; P = 0.2868, Dn = 11 replicates, *P = 0.0120. En = 9 replicates, **P = 0.0097, Fn = 11 replicates; **P = 0.0055
Next-generation neuropeptide Y receptor small-molecule agonists inhibit mosquito-biting behavior

June 2024

·

34 Reads

·

2 Citations

Background Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses. Methods Using structure–activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. Results Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified three compounds that reduced blood-feeding from a live host when fed to mosquitoes at a dose of 1 μM—a 100-fold improvement over the original reference compound. Conclusions Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito–human host interactions that lead to pathogen transmission. Graphical Abstract


Figure 1: Structure-guided design to synthesize novel NPYLR7 agonists
Figure 2: Small molecule NPYLR7 agonists tested in vivo
Figure 3: Miniport olfactometer screening assay to identify compounds that suppress attraction to human
Figure 4: Novel NPYLR7 agonists suppress blood feeding from a live host when fed at 1 µM dose
Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior

March 2024

·

51 Reads

Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like Receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small molecule NPYLR7 agonists that suppress host-seeking and blood feeding when fed to mosquitoes at high micromolar doses. Using structure activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified 3 compounds that suppressed blood feeding from a live host when fed to mosquitoes at a 1 μM dose, a 100-fold improvement over the original reference compound. Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito/human host interactions that lead to pathogen transmission.


Figure 2: Orco mutant mosquitoes display enhanced heat-seeking behavior. (A) Schematic of female body parts that express Orco. (B) Heat maps showing mean mosquito occupancy for the indicated genotypes on the Peltier (dotted lines) and surrounding area at indicated Peltier temperature during seconds 90-180 of each stimulus period. (C) Mean ± SEM percent of mosquitoes of indicated genotypes on Peltier (top) during the 36°C trial (bottom). A 20 second pulse of CO2 was applied at the beginning of each stimulus period. (D) Percent of mosquitoes of indicated genotypes on Peltier during seconds 90-180 of stimuli of indicated temperature (mean ± SEM, n = 9 trials per genotype; datapoints marked with * indicate that the knockout mutant differs significantly from all other tested genotypes within each tested temperature at p < 0.05; one-way ANOVA with Tukey's HSD post hoc test). (E -G) Mean dwell time (E), landing frequency (F), and takeoff frequency (G) of indicated genotypes on the Peltier surface during the 36°C trial (n = 9 trials/genotype). (H) Schematic representation of the modified heat-seeking assay (28 cm 3 ) in the presence of DEET. (I) Percent of mosquitoes of indicated genotype and treatment groups heat-seeking during a 40°C trial (n = 6-10 trials/genotype). Data are plotted as scatter-box plots (individual data points, median as horizontal line, interquartile range as box) for (E,F,G,I). Data labeled with different letters differ significantly (p < 0.05; one-way ANOVA with Tukey's HSD post hoc test at each tested temperature).
Figure 8: Ir140 contributes to heat-seeking behavior and is required for the enhanced Orco mutant heatseeking behavior (A) Schematic of Aedes aegypti Ir140 and Orco loci. Arrows indicate Ir140 mutant alleles in wildtype and Orco mutant backgrounds. Introns are not drawn to scale. (B,C) Percent of mosquitoes of indicated genotype on Peltier
Cross-modal sensory compensation increases mosquito attraction to humans

October 2023

·

175 Reads

·

1 Citation

Sensory compensation is a process that allows individuals with a loss of one sense, for instance hearing or vision, to adapt to changes in their sensory abilities. Where this phenomenon has been observed, there is enhanced perception by another sense to compensate for deficiency of the lost sense. Such compensation is important for humans and non-human animals that use multisensory integration for effective navigation and the execution of vital tasks. Among these, female mosquitoes are sensory specialists that rely heavily on integrating multiple human-emitted cues in their quest for a suitable host to obtain a blood meal. Here, we identify a previously undescribed mechanism of sensory compensation in female Aedes aegypti mosquitoes. Mutant mosquitoes lacking the odorant receptor co-receptor Orco show specific enhancement in heat-seeking behavior. This sensory compensation does not require the antenna, which was previously assumed to be the primary mosquito thermosensitive organ. Instead, we found that the tips of the forelegs are required to detect heat, and that the heightened sensitivity in heat detection is mediated by increased neuronal activity in foreleg sensory neurons, which are distant from the head appendage neurons that express Orco. By comparative gene expression analysis in wildtype and Orco mutant legs, we identify Ir140, a foreleg-enriched member of the Ionotropic Receptor (IR) superfamily of sensory receptors, as strongly upregulated in Orco mutant legs. Emphasizing the important role of IRs in thermosensation, we find that mutant mosquitoes lacking the IR co-receptor, Ir25a, lose all responses to heat, and Ir140 mutants show strong deficits in responding to human skin temperatures. We generated an Ir140, Orco double mutant and show that these animals lose the remarkable sensory compensation seen in Orco mutants. This strongly suggests that upregulation of Ir140 in the foreleg is the mechanism of sensory compensation in Orco mutants. Odorant receptor expression is sparse in legs, suggesting an indirect, long-range mechanism of sensory compensation. Our findings reveal a novel compensatory mechanism in which loss of one sensory modality in female Aedes aegypti mosquitoes results in greater sensitivity in another to maintain the overall effectiveness of their host-seeking behavior, further enhancing their status as the most dangerous predator of humans.


Two novel, tightly linked, and rapidly evolving genes underlie Aedes aegypti mosquito reproductive resilience during drought

February 2023

·

97 Reads

·

13 Citations

eLife

Female Aedes aegypti mosquitoes impose a severe global public health burden as vectors of multiple viral pathogens. Under optimal environmental conditions, Aedes aegypti females have access to human hosts that provide blood proteins for egg development, conspecific males that provide sperm for fertilization, and freshwater that serves as an egg-laying substrate suitable for offspring survival. As global temperatures rise, Aedes aegypti females are faced with climate challenges like intense droughts and intermittent precipitation, which create unpredictable, suboptimal conditions for egg-laying. Here we show that under drought-like conditions simulated in the laboratory, females retain mature eggs in their ovaries for extended periods, while maintaining the viability of these eggs until they can be laid in freshwater. Using transcriptomic and proteomic profiling of Aedes aegypti ovaries, we identify two previously uncharacterized genes named tweedledee and tweedledum, each encoding a small, secreted protein that both show ovary-enriched, temporally-restricted expression during egg retention. These genes are mosquito-specific, linked within a syntenic locus, and rapidly evolving under positive selection, raising the possibility that they serve an adaptive function. CRISPR-Cas9 deletion of both tweedledee and tweedledum demonstrates that they are specifically required for extended retention of viable eggs. These results highlight an elegant example of taxon-restricted genes at the heart of an important adaptation that equips Aedes aegypti females with 'insurance' to flexibly extend their reproductive schedule without losing reproductive capacity, thus allowing this species to exploit unpredictable habitats in a changing world.


Differential mosquito attraction to humans is associated with skin-derived carboxylic acid levels

October 2022

·

311 Reads

·

86 Citations

Cell

Some people are more attractive to mosquitoes than others, but the mechanistic basis of this phenomenon is poorly understood. We tested mosquito attraction to human skin odor and identified people who are exceptionally attractive or unattractive to mosquitoes. These differences were stable over several years. Chemical analysis revealed that highly attractive people produce significantly more carboxylic acids in their skin emanations. Mutant mosquitoes lacking the chemosensory co-receptors Ir8a, Ir25a, or Ir76b were severely impaired in attraction to human scent, but retained the ability to differentiate highly and weakly attractive people. The link between elevated carboxylic acids in "mosquito-magnet" human skin odor and phenotypes of genetic mutations in carboxylic acid receptors suggests that such compounds contribute to differential mosquito attraction. Understanding why some humans are more attractive than others provides insights into what skin odorants are most important to the mosquito and could inform the development of more effective repellents.


Non-canonical odor coding in the mosquito

August 2022

·

406 Reads

·

128 Citations

Cell

Aedes aegypti mosquitoes are a persistent human foe, transmitting arboviruses including dengue when they feed on human blood. Mosquitoes are intensely attracted to body odor and carbon dioxide, which they detect using ionotropic chemosensory receptors encoded by three large multi-gene families. Genetic mutations that disrupt the olfactory system have modest effects on human attraction, suggesting redundancy in odor coding. The canonical view is that olfactory sensory neurons each express a single chemosensory receptor that defines its ligand selectivity. We discovered that Ae. aegypti uses a different organizational principle, with many neurons co-expressing multiple chemosensory receptor genes. In vivo electrophysiology demonstrates that the broad ligand-sensitivity of mosquito olfactory neurons depends on this non-canonical co-expression. The redundancy afforded by an olfactory system in which neurons co-express multiple chemosensory receptors may increase the robustness of the mosquito olfactory system and explain our long-standing inability to disrupt the detection of humans by mosquitoes.


Figure 3. The persistent state is specific to host seeking. (A-C) Response of non-blood-fed female (A), blood-fed female (B), and male (C) Gr3 > CsChrimson mosquitoes to the indicated stimuli, plotting each behavior from 2 min before to 15 min after stimulus onset (n=98/group, average of 3 stimulus presentations/mosquito). (D,E) Quantification of walking (D) and probing (E) from data in (A-C) for 5 min after stimulus onset. (F-H) The behavioral response of males of the indicated genotype to the indicated stimuli, plotting each behavior from 2 min before to 15 min after stimulus Figure 3 continued on next page
A persistent behavioral state enables sustained predation of humans by mosquitoes

May 2022

·

81 Reads

·

25 Citations

eLife

Predatory animals pursue prey in a noisy sensory landscape, deciding when to continue or abandon their chase. The mosquito Aedes aegypti is a micropredator that first detects humans at a distance through sensory cues such as carbon dioxide. As a mosquito nears its target it senses more proximal cues such as body heat that guide it to a meal of blood. How long the search for blood continues after initial detection of a human is not known. Here we show that a 5-second optogenetic pulse of fictive carbon dioxide induced a persistent behavioral state in female mosquitoes that lasted for more than 10 minutes. This state is highly specific to females searching for a blood meal and was not induced in recently blood-fed females or in males, who do not feed on blood. In males that lack the gene fruitless , which controls persistent social behaviors in other insects, fictive carbon dioxide induced a long-lasting behavior response resembling the predatory state of females. Finally, we show that the persistent state triggered by detection of fictive carbon dioxide enabled females to engorge on a blood meal mimic offered up to 14 minutes after the initial 5-second stimulus. Our results demonstrate that a persistent internal state allows female mosquitoes to integrate multiple human sensory cues over long timescales, an ability that is key to their success as an apex micropredator of humans.


Citations (65)


... A study of D. melanogaster brains from different sleep and wakefulness states revealed that glial cells integrate homeostatic and circadian processes [8]. Furthermore, blood-feeding causes Aedes aegypti mosquitoes to suppress their appetite during which time there are extensive transcriptional changes in glia but not neurons [9]. Lee and colleagues add a new piece: glia's rapid evolution in D. sechellia highlights their role as evolutionary innovators in the brain. ...

Reference:

Glial cells diverge in fly brain evolution
Mosquito Cell Atlas: A single-nucleus transcriptomic atlas of the adult Aedes aegypti mosquito

... The profound sexual dimorphism of Aedes aegypti mosquitoes is fundamental to the public health threat they pose to humans. Mosquitoes are attracted to human cues, including exhaled carbon dioxide (CO 2 ), body heat, and skin odor [8][9][10][11] . Only females feed on blood, which provides the proteins and other nutrients that they require for reproduction. ...

Cross-modal sensory compensation increases mosquito attraction to humans
  • Citing Article
  • January 2025

Science Advances

... Brain evolution has repeatedly solved problems of far higher dimensionality than the four dimensions required here, olfaction being a prime case in point. The similarity spaces for mapping olfactory stimuli are irreducibly high-dimensional (Cleland, 2008), and although the exact number of dimensions involved is still being studied, they amount to many multiples of four (Magnasco, Keller, & Vosshall, 2015;Mamlouk & Martinetz, 2004). ...

On the dimensionality of olfactory space

... The function of AaARLP is crucial for the virus infection process, highlighting key factors in vectorial capacity, such as the pathogen's extrinsic incubation period and vector competence (36). Developing small molecules targeting AaARLP could potentially serve as a mosquito vaccine to interrupt vectorial capacity (18,37,38). While limitations in mosquito research, such as the availability of antibodies and suitable agonists/antagonists, exist, we were able to achieve significant findings through alternative approaches. ...

Next-generation neuropeptide Y receptor small-molecule agonists inhibit mosquito-biting behavior

... Las enfermedades del dengue, zika y chikunguña, transmitidas por Aedes spp. están influenciadas por diversos factores, entre ellos los factores climáticos (Barreto et al., 2020;Hussain & Dhiman, 2022;Ibrahim et al., 2020;Omar et al., 2021;Venkataraman et al., 2023). Los resultados de la investigación basados en la revisión de estudios recientes evidencian la relevancia de los factores en la propagación de estas enfermedades en Sudamérica. ...

Two novel, tightly linked, and rapidly evolving genes underlie Aedes aegypti mosquito reproductive resilience during drought

eLife

... Each sensillum contains one or multiple olfactory sensory neurons which have odorant binding protein receptors on their surface that bind to specific odor molecules and result in the depolarization of the neuron [32]. Single sensillum recordings can provide information about the specific compound or compounds that an individual sensillum on the antenna is capable of detecting [33]. Although sensilla may be morphologically similar, each sensillum on the antenna has olfactory receptors tuned to detect specific compounds. ...

Single Sensillum Recordings in the Insects Drosophila melanogaster and Anopheles gambiae
  • Citing Article
  • February 2010

Journal of Visualized Experiments

... Among them, volatile organic compounds (VOCs) produced by human skin microbiota act as primary sensory signals (Lucas-Barbosa et al. 2022;Blanken et al. 2024). Therefore, all olfactory traps developed to date operate in a similar manner, exploiting the anthropophilic behavior of Ae. albopictus females by attracting host-seeking mosquitoes through the combined release of CO₂ and olfactory attractants derived from human skin microbiota, such as carboxylic acids (e.g., hexanoic acid), ammonia, and lactic acid (De Obaldia et al. 2022;Lucas-Barbosa et al. 2022). Once attracted, female mosquitoes are drawn in by electric ventilation and captured in collection bags (Jaffal et al. 2023). ...

Differential mosquito attraction to humans is associated with skin-derived carboxylic acid levels

Cell

... The panel of the tested 23 ligands (Table 1) included control ligands, aimed to indicate choice of the correct sensillum among ac1-4 types [17,18,[31][32][33][34][35][36][37]. Stimuli were diluted either in water or ethanol (Sigma Aldrich, St. Louis, MO-USA) depending on their solubility (Table 1) and then prepared as described by Silbering et al. [17], using 20 μL of 1% dilutions or 30 μL of 10 μg/μL for phenylacetic acid. ...

Non-canonical odor coding in the mosquito

Cell

... [65], 10 minutes [66], and even longer [67]. Together, these behavioral experiments suggest that insects have mechanisms for maintaining persistent memories of an odor experience on time scales of at least 10 seconds. ...

A persistent behavioral state enables sustained predation of humans by mosquitoes

eLife

... At least four distinct and potentially overlapping mechanisms that involve the sensory periphery can be invoked to explain host shifts: 1. A change in the number of sensory sensilla and associated receptor neurons, resulting in increased or decreased sensitivity to attractants or repellents [65] and Culicidae [4]. Also produced by chickens [66]. ...

Differential mosquito attraction to humans is associated with skin-derived carboxylic acid levels