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The Taste of Blood in Mosquitoes

Veronica Jové, Zhongyan Gong, Felix J.H. Hol, Zhilei Zhao, Trevor R. Sorrells, Thomas S. Carroll, Manu Prakash, Carolyn S. McBride, Leslie B. Vosshall

Posted on: 23 April 2020

Preprint posted on 27 February 2020

Article now published in Neuron at http://dx.doi.org/10.1016/j.neuron.2020.09.019

I’ll have a blood meal to go–no milk, no sugar: Female Aedes aegypti mosquito stylet neurons drive discrimination between blood and nectar based on neuronal activation by blood components

Selected by Vaibhav Menon

Background

Aedes aegypti is is a species of mosquito that is a particularly effective vector for viruses that cause diseases including yellow fever, dengue fever, chikungunya fever, and Zika fever [1]. These diseases are transmitted when the female mosquito bites humans in search of a blood meal. This preference for a blood-meal, however, is context-dependent. Sugar from nectar provides an energy source for the insect, but to progress egg development, mated female mosquitoes require blood. Additionally, the anatomical program by which a mosquito feeds on blood has been demonstrated to be distinct from its sugar-feeding tract. Nectar, a sugar-rich food source present in flowers, is sensed by the labium whereas blood is consumed by the sharp needle-like labrum organ, also known as the stylet. While previous studies have shown that the blood-feeding behavior can be observed in the context of human cues such as CO2 plumes or heat, it is not clear how blood specifically is sensed before consumption [2]. In this preprint, the authors comprehensively demonstrate the sexually dimorphic expression of gustatory receptor neurons (GRNs) on the stylet that poise the female to respond uniquely to the components of blood, including glucose, NaHCO3, NaCl, and ATP. In doing so, they clearly illustrate that blood sensing is a complex integration of multiple, distinct taste qualities mediated by at least two classes of ionotropic receptors (Irs).

Key findings:

Blood-sensing and sugar-sensing are separable behaviors

Feeding assays demonstrated that the volume of blood consumed by the female mosquito was triple that of sucrose-consumption. Blood localized to the midgut after consumption, whereas sucrose localized to the crop. These observations pointed to a difference in behavioral programs driving blood-feeding and nectar-feeding. In Drosophila melanogaster, Gr5aand Gr64f are established sugar-sensing neurons. The closest ortholog to these in mosquitos is Gr4. Thus, the authors used CRISPR-Cas9 genome editing to insert the binary expression construct QF2 at the Gr4 locus to gain genetic access to this potential sweet-tasting neuron. Indeed, they confirmed its role in responding to sugar by chemogenetically activating this population and observing feeding behavior responses to water comparable to those of sucrose. So how does blood-sensing fit in?

To probe at the evaluation of blood prior to consumption, the authors noted that in the presence of human cues CO2 and heat, females would reliably feed to engorgement on blood and an ATP/saline solution, but not sucrose or saline alone. The presence of human cues, in other words, is followed by a separate evaluation of the food source that allows for selection of blood or blood components over sugar.

 

Neural expression and projection patterns are sex-specific and organ-specific, respectively

Examination of the stylet under pan-neuronal GCaMP expression, nuclear and dendritic staining reveal significantly more cell bodies and dendritic processes in the female stylet than the male stylet. Dye-fill experiments comparing stylet neurons to labium neurons illustrate a non-overlapping projection region to the subesophageal zone (the first projection of taste information in insects) from the two organs.

 

Mosquito behavior and stylet neuron activity in response to blood can be broken down component-wise

GCaMP6s responses to repeated presentations of blood showed non-adapting, robust calcium signals in a significant number of stylet neurons. Water failed to elicit such a response. Using a combination of 4 components of blood that have shown to increase likelihood of engorgement–ATP, glucose, NaHCO3, NaCl–the authors observed calcium responses similar to that of blood. Observation of responses to these components individually demonstrated the component-wise stylet response. Neurons could be clustered based on the component they responded most robustly to, creating groups of neurons that responded uniquely to ATP, NaHCO3, NaCl, a population that responded to all 3, and a population that did not respond to any of these. Through this experiment, the authors suggest that the blood response can understood as an integration of information from different taste modalities.

 

Blood-sensing neurons localized to stylet, sugar sensing neurons localized to labium

The authors then analyzed RNA-seq data of stylet tissue to identify significantly enriched genes in the female stylet and labium. They identified two ionotropic receptors, Ir7a and Ir7f, that were unique to the female stylet. After gaining binary expression control and genetic access of these neurons, functional imaging using the 4 components of blood revealed Ir7a responses were most robust in the presence of NaHCO3. Ir7f neurons, on the other hand, responded most robustly to the mix of all 4 components. These neurons reflected the response profile of the integrator cluster of neurons identified in pan-neuronal GCaMP6s expression experiments of the stylet. RNA-seq expression analysis further revealed expression in the labium but notably not the stylet of orthologs of known sugar receptors in D. melanogaster, suggesting that blood-sensing and sugar-sensing behaviors are also distinct in the neuronal organization that governs each program.

 

Why I liked this paper:

This paper was an exhaustive study of a previously understudied organ of the mosquito. Given the role blood-feeding has on the proliferation of deadly diseases that debilitate millions, this study also struck me as a compelling and important undertaking. I chose this paper because I am interested in gustatory behavior and integration of sensory information associated with feeding. Mosquitos demonstrate two totally different feeding behaviors, so a model incorporating segregation of taste organs and thus neuronal input would be a simple, yet elegant explanation for how these behaviors diverge. At a minimum, this thorough characterization of the stylet provides a critical foundation for which blood-feeding and behavior can be further explored.

 

Future Directions:

  1. Given the stylet’s unique role in blood-feeding, what information do you think the population of neurons that failed to respond to blood may be sensing? You mentioned potential thermosensory or mechanosensory roles. If these neurons were mechanosensory, I would have expected to see them activate during feeding anyway.
  2. The labrum is one of the mouthparts of the mosquito that are involved in processes of feeding. While the labrum is the mouthpart that pierces skin, are the other mouthparts receiving input from the periphery that might influence blood-feeding?

 

References

1.Powell JR. Mosquito-Borne Human Viral Diseases: Why Aedes aegypti?. Am J Trop Med Hyg. 2018;98(6):1563–1565. doi:10.4269/ajtmh.17-0866

2. McMeniman, C.J., Corfas, R.A., Matthews, B.J., Ritchie, S.A., and Vosshall, L.B. (2014). Multimodal integration of carbon dioxide and other sensory cues drives mosquito attraction to humans. Cell 156, 1060-1071.

Tags: aedes, blood, drosophila, gustatory, mosquito, taste

doi: https://doi.org/10.1242/prelights.19179

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Author's response

Veronica Jové shared

  1. Given the stylet’s unique role in blood-feeding, what information do you think the population of neurons that failed to respond to blood may be doing? You mentioned potential thermosensory or mechanosensory roles. If these neurons were mechanosensory, I would have expected to see them activate during feeding anyway. Do you think some fraction of these neurons may act as an inhibitory off-switch for blood-sensing when the mosquito reaches engorgement? 

In this study we focused on chemosensory blood components that promote blood-feeding behavior. However, we hypothesize that at least some of the remaining stylet neurons respond to additional ligands that the mosquito could encounter while blood feeding. These could include heat and viscosity as you noted, and our preliminary data show that 2 neurons in every stylet respond to water/the absence of osmolarity. The stylet could also detect bitter feeding deterrents that can be added to blood to prevent blood feeding (Dennis et al., 2019). If the stylet does respond to these bitter compounds, then we predict it would activate an aversive pathway that ultimately overrides the appetitive taste of blood.

We still don’t know if stylet neurons receive feedback from visceral organs that signal satiety. Early mosquito studies found that severing the ventral nerve cord causes the mosquito to overeat and occasionally burst (Gwadz, et al., 1969)! Therefore, we predict that stylet neurons can’t intrinsically act as an off-switch. Upon taking a full meal, signals from the ventral nerve cord may influence the activity of stylet neurons and/or motor circuitry that control pumping.

 

  1. The labrum is one of the mouthparts of the mosquito that are involved in processes of feeding. While the labrum is the mouthpart that pierces skin, are the other mouthparts receiving input from the periphery that might influence blood-feeding?

To understand how blood is detected, we focused on the labrum (referred to as the stylet in our study) because it is the only innervated appendage that directly contacts blood underneath the skin. Since the labium remains on the surface of the skin, we know that it does not directly taste blood during normal blood-feeding behavior. However, the labium could be tasting chemosensory ligands present on human skin, which may in turn influence blood-feeding behavior. In our RNA-seq data set, we found the labium expresses olfactory receptors, in addition to ionotropic and gustatory receptors. It would be really interesting to see if the “taste” of skin during blood feeding is integrated with the taste of blood to make the meal even more appetitive. Nonetheless, we know that detection of skin by the labium is not required for blood feeding because we replaced human skin with an inert piece of parafilm in our blood-feeding behavior assay.

References 

Dennis, E.J., Goldman, O.V., and Vosshall, L.B. (2019). Aedes aegypti mosquitoes use their legs to sense DEET on contact. Curr Biol 29, 1551-1556.

Gwadz, R. W. (1969). Regulation of blood meal size in the mosquitoJournal of Insect Physiology, 15(11), 2039–2044. doi:10.1016/0022-1910(69)90071-7

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