ResearchMetabolic and Behavioral Physiology
RIKEN ECL Research Team

Mosquitoes, insects familiar to everyone, feed on the blood of humans and other animals (hosts). In addition to leaving behind their characteristic buzzing and itchy bites, they transmit a wide range of pathogens directly into the bloodstream and are recognized as the deadliest animals to humans worldwide. Despite long-standing description of mosquito behavior and ecology, and numerous eradication efforts over centuries, a world free from mosquito bites has yet to be realized. Consequently, diverse research programs continue to explore strategies for mosquito control.

Our laboratory centers on blood feeding, with particular emphasis on:

• 1.The blood-feeding behavior itself, which represents the critical step through which pathogens are transmitted to the host
• 2.The physiological processes, including metabolic regulation, that underlie the utilization of ingested blood for egg maturation

By addressing these questions, we aim to advance a mechanistic understanding of mosquito biology. Insights gained from this work are expected to inform strategies not only to modulate blood-feeding behavior but also to intervene directly in reproductive processes, thereby suppressing or enhancing egg production.

Furthermore, the mechanisms by which mosquitoes digest, absorb, and metabolize blood-derived nutrients exhibit striking parallels with how other animals process dietary nutrients to sustain vital functions. Thus, elucidating blood metabolism in mosquitoes not only deepens our knowledge of their unique biology but also contributes to a broader understanding of fundamental principles underlying nutrition and metabolism across animal species

Our model species is the mosquito Aedes aegypti. Native to tropical and subtropical regions, this mosquito was among the first in its genus to have its genome sequenced and has since become a central subject of molecular and genetic studies. Although Ae. aegypti has not established stable populations in Japan, it is a close relative of the more familiar Aedes albopictus (the Asian tiger mosquito). Ae. aegypti can be stably reared in the laboratory, and in recent years genetic modification and genome editing techniques have become available for this species. Importantly, only adult females in the reproductive phase ingest blood meals, whereas males and newly emerged females do not engage in blood feeding.

Mosquito blood feeding is typically completed within just a few minutes, after which females reach a body weight approximately 2.5 times their original mass—an exceptionally dynamic mode of feeding.

After landing on the host’s skin, female mosquitoes may repeatedly insert and withdraw their stylet while moving across the surface, a behavior known as probing. Once a blood vessel is successfully found, rapid ingestion begins. However, if aversive compounds such as bitter substances are detected, the mosquito withdraws its stylet and aborts feeding. Thus, not all mosquitoes attracted to a host ultimately blood feed; rather, they first “taste” the blood to assess whether it is suitable for ingestion.

About 65 years ago, adenosine triphosphate (ATP) present in host blood was identified as a factor that triggers and promotes blood feeding. Yet the molecular mechanisms by which mosquitoes sense ATP remain elusive. Similarly, the mechanisms underlying the termination of feeding have not been fully elucidated. Because mosquitoes stop feeding before their midgut is overfilled, it has long been suggested that abdominal distension provides a mechanical signal to limit intake, but the molecular basis of this process has remained unclear.

Our recent work demonstrated that fibrinopeptide A, generated during host blood coagulation, act as signals that terminate blood feeding. In the presence of this peptide, mosquitoes cease ingestion before reaching full satiety. This finding suggests that, in addition to mechanical cues such as abdominal distension, mosquitoes detect this peptide in the midgut to fine-tune the timing of feeding termination.

We aim to elucidate how mosquitoes sense host blood components through both proboscis and midgut to regulate the initiation and termination of feeding, and how they perceive aversive compounds such as bitterness and other tastes.

Female mosquitoes lay approximately 100 eggs about three days after a blood meal. Before feeding, immature oocytes are present in the ovaries, and upon blood ingestion, yolk synthesis and deposition are initiated, leading to the development of mature eggs. After oviposition, the next oocytes derived from germline stem cells remains arrested in an immature state until the subsequent blood meal triggers their maturation. Thus, throughout their lifetime, females undergo several times of blood feeding and alternate between a “blood-seeking mode,” in which they seek a host while carrying immature eggs, and an “egg-maturation mode,” in which they utilize the acquired blood to mature eggs. Notably, females in the egg-maturation mode no longer require additional blood and therefore do not exhibit host seeking behavior. Understanding the mechanisms of egg maturation is therefore crucial not only for regulating mosquito reproductive output but also for developing strategies to artificially induce the non-host-seeking “egg-maturation mode” and thereby suppress blood feeding behavior.

Egg maturation proceeds through the coordinated actions of multiple organs and hormones. Once host blood enters the midgut, the brain releases several hormones to the ovaries. In response, the ovaries secrete ecdysone, a well-known molting hormone, to the fat body (the functional equivalent of the mammalian liver and white adipose tissue). Ecdysone signaling initiates vitellogenesis in the fat body, and the synthesized yolk proteins are subsequently transported to the ovaries and incorporated into developing oocytes. In this way, the brain, midgut, fat body, ovaries, and the circulating hemolymph act in concert to ensure the smooth progression of egg maturation.

Meanwhile, the ingested host blood is digested gradually over nearly 50 hours in the midgut. Some of its components function as signals to trigger egg maturation, whereas others serve as building blocks for yolk synthesis. Although the ecdysone centered regulation of vitellogenesis has been extensively studied, many questions remain unresolved, including the mechanism by which host seeking behavior is suppressed during the egg-maturation mode and how females switch between the blood-seeking and egg-maturation modes.

Our laboratory focuses on elucidating the regulatory mechanisms underlying this behavioral switch, integrating perspectives from neuroscience, metabolism, and endocrinology. In particular, we have directed attention to amino acids and proteins abundant in host blood. Traditionally, the 20 amino acids have often been treated as a single group, but our studies suggest that individual amino acids exhibit distinct dynamics, undergo time-specific metabolism and fulfill unique functions. In addition to characterizing amino acid metabolism, we aim to comprehensively analyze hormones exchanged among different organs along the timeline of egg maturation, ultimately linking metabolic and endocrine states to behavioral regulation.