Anopheles arabiensis

What do you think is the deadliest animal in the world?

Sharks? Nope.

Snakes? Nope.

Humans? Getting closer, but no.

Mosquitoes? Ding, Ding, Ding! We have a winner. If you give them credit for malaria and the other diseases that they carry, mosquitoes are responsible for roughly 725,000 deaths annually according to the World Health Organization.

Mosquitos are considered “vectors” because they can carry diseases and transmit them to humans. There are over 2500 species of mosquitoes found on 6 continents, but not all mosquitoes are created equal. There is incredible diversity in their abilities to carry and transmit disease, a property called vectorial capacity. Vectorial capacity can be affected by their geographic range, when and if a mosquito species bites humans and animals, how and when mosquitoes reproduce, and even their resistance to insecticides. One approach to look at how mosquitoes change is genomics. Genomics is the study of the structure and function of an organism’s total genetic material – all of its genes encoded in DNA made up of A, C, T, and G nucleotides. This approach allows scientists to rapidly pull out some of the most relevant genes, or groups of genes, that may contribute to mosquitoes’ ability to transmit disease. For example, genomics has shown us that mosquitoes like Anopheles gambiae and Aedes aegypti, some of the most effective disease vectors, are constantly evolving. These questions are the interest of vector biologists – scientists who study mosquitoes and other insects that transmit disease.

Science in the News got a chance to chat with two vector biologists in the Harvard-MIT community. We talked with them about why they chose to study mosquitoes and vector-borne diseases, what some of the major challenges are for vector biology now, and how they envision targeting mosquitoes to reduce disease.

Dan Neafsey, PhD leads the Malaria Genome Sequencing and Analysis Group at the Broad Institute of MIT and Harvard. In this capacity, he oversees projects aimed at decoding and analyzing the genomes of the parasites that cause malaria (Plasmodium falciparum, among others) as well as the mosquitoes that transit them to humans.

Perrine Marcenac is a third-year PhD student in the Biological Sciences in Public Health program in the Harvard School of Public Health (HSPH). She works on mosquito fertility in Dr. Flaminia Catteruccia’s lab, and makes trips to Burkina Faso, in West Africa, for fieldwork.

How did you find your way into vector biology and disease?

Perrine: I began studying mosquitoes because, when I began my PhD, I was interested in studying infectious diseases, and I was particularly drawn to the labs studying malaria at HSPH. I joined Flaminia’s lab, studying mosquito fertility, because I found it brought up fascinating questions on how we can study interactions within the mosquito vector. Malaria-transmitting mosquitoes need to take a blood meal to pick up and transmit malaria, but they also require a blood meal to produce eggs. In this way, we have the unique opportunity to look at interplay between these factors in Anopheles mosquitoes in the Catteruccia lab.

Dan: My PhD project focused on genome evolution in pufferfish. It was a great system for learning the principles of molecular evolution and population genetics, and pufferfish do kill people when they are prepared by inexpert sushi chefs and eaten (Homer Simpson was famously poisoned by Fugu [pufferfish] in one episode of “The Simpsons”). But, I wanted to work in an area with greater potential for translation into human health benefits. When I finished my PhD, the malaria community was about to progress from having one sequenced P. falciparum genome to three! It was an exciting opportunity to do a population genomic analysis of variation in an organism with an arguably greater impact on human health than pufferfish.

Figure 1 Disease-bearing mosquitoes.  Arabiensis and gambiae photos by James Gathany, from the CDC’s Public Health Image Library. Aedes aegypti photo by Muhammed Mahdi Karim, licensed under GNU Free Document License Version 1.2 only.

What has been the biggest challenge in working on mosquitoes and malaria parasites?

Dan: Plasmodium falciparum is a constant challenge. It has one of the most extreme genomes of any organism in terms of composition; its genome is 81% A and T nucleotides, as opposed to the more typical equitable mix of A, T, G, and C. Sequencing and analysis of a genome with so many A’s and T’s is always challenging, and requires customization of existing methodologies.

Perrine: The biggest challenge for me thus far, both in the field and in the lab, has been that mosquitoes are complex organisms whose fertility, behavior, susceptibility to infection, and other characteristics important for vector competence are strongly influenced by a number of factors throughout larval and adult development. All these influences need to be considered when conducting experiments using these mosquitoes, particularly in the field where variability is greatest.

Who’s evolving faster and why: mosquitoes or malaria parasites?

Dan: Both mosquitoes and malaria parasites have demonstrated their capacity to quickly evolve resistance to drugs and insecticides. But, most Anopheles mosquitoes appear to have a much larger long-term effective population size, which may make them slightly more sensitive to subtle evolutionary pressures.

What makes a particular mosquito species a better disease vector than others?

Perrine: A number of characteristics can make a mosquito species a better disease vector than others. These include a preference for biting humans (anthropophilic) over animals (zoophilic) and how the biting behavior corresponds to human behavior. Anopheles gambiae are indoor biters, for example, whereas Anopheles arabiensis are outdoor biters – some malaria vectors may bite at different times of the day. The reproductive rate of a given mosquito species also affects disease transmission (more mosquitoes = greater transmission).

Figure 2 There are around 3000 mosquito species found worldwide, this map illustrates the range of only those within the Anopheles family.  Species discussed in this article are found primarily in sub-Saharan Africa and are shown in bold.

In your opinion, what are the biggest questions that research in your field aims to answer?

Dan: Mosquito genomics has the potential to contribute to our understanding of vectorial capacity. Only a tiny fraction of all Anopheles species transmit human malaria. The capacity to transmit malaria is a complicated, composite trait that is a function of behavior, immunity, life history, and other factors. Genomics has the capacity to generate hypotheses and launch studies in all of these biological realms that contribute to vectorial capacity.

Moving forward, what do you envision as a strategy for vector control and malaria eradication?

Dan: Much of the success of previous malaria elimination campaigns is attributable to breaking the cycle of disease transmission through thorough vector control. Controlling vector populations via diverse means, in a rational way that does not engender the evolution of insecticide resistance or otherwise undermine the efficacy of the control measures, will be critical for eliminating malaria from disease-endemic regions.

Many thanks to our contributors Dan and Perrine. Vector-borne diseases remain a major problem of our time. These diseases have killed 14 people, just in the time it likely took to read this article.  Luckily, we have scientists bringing together many disciplines related to vector biology – from population biology, to genetics and genomics, to chemistry, ecology, evolutionary biology, and epidemiology and immunology. Hidden within this complex system are solutions to controlling mosquitoes and controlling disease.

Rachel Cotton is a PhD student in the Harvard Immunology Program.

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