Mosquitoes are considered one of the most dangerous animals on earth because of their broad distribution and the many pathogens they transmit to humans. Some of the most important human diseases in tropical and temperate regions of the planet are caused by mosquito-borne pathogens. Malaria, dengue, and filariasis, among other mosquito-borne diseases, kill or sicken millions of people worldwide every year.

Mosquito-borne pathogens are transmitted to the vertebrate host, such as a human, when the mosquito bites the host in search of blood. The proteins found in blood are essential for female mosquitoes: without it, they lack the resources to create eggs. Greater knowledge of the biological processes involved in the mosquito life cycle could lead to new or improved strategies to control mosquito populations.     

Dr. Patricia Scaraffia, Associate Professor at the Tulane University School of Public Health and Tropical Medicine, has dedicated her career to understanding the metabolism of the mosquito Aedes aegypti that carries the pathogens responsible for dengue, Zika, chikungunya, and yellow fever to humans. NIAID reached out to Dr. Scaraffia about her team’s research. 

What got you interested in studying mosquito metabolism?

I have studied the metabolism of insects that are vectors of pathogens causing human diseases since I was a graduate student at the Universidad Nacional de Cordoba, in Argentina. My Ph.D. dissertation was focused on the energy metabolism in Triatomine insects, vectors of Trypanosoma cruzi, the etiological agent of Chagas´ disease. After my dissertation, I participated as a speaker in a two-week course for PhD students entitled Biochemistry and molecular biology of insects of importance for public health. During the course, Argentinian professors encouraged me to contact the late Dr. Michael A. Wells, a leader in insect metabolism, and apply for a postdoctoral training in his lab. Soon after, I joined Dr. Wells´s lab at the University of Arizona as a research associate and opened a new line of investigation in his lab. Since then, I have never stopped working on A. aegypti mosquito metabolism. I am passionate and curious about the tremendous complexity of mosquito metabolism. It is a fascinating puzzle to work on. It constantly challenges me and my research team to think outside the box when trying to decipher the unknowns related to mosquito metabolism.

Dr. Patricia Scaraffia's work focuses on the secrets of mosquito metabolism.

Credit: Dr. Patricia Scaraffia

What are the metabolic challenges faced by mosquitoes after feeding on blood?

Female mosquitoes are a very captivating biological system. It is during blood feeding that female mosquitoes can transmit dangerous, and sometimes lethal, pathogens to humans. Interestingly, the blood that the females take could be twice their body weight, which is impressive. Female mosquitoes have evolved efficient mechanisms to digest blood meals, eliminate excess water, absorb and transport nutrients, synthesize new molecules, metabolize excess nitrogen, remove nitrogen waste, and successfully lay eggs within 72 hours! Despite significant progress in understanding how females overcome these metabolic challenges, we have not yet fully elucidated the intricate metabolic pathways, networks, and signaling cascades, nor the molecular and biochemical bases underlying the multiple regulatory mechanisms that may exist in blood-fed female mosquitoes. 

What are the greatest potential benefits of understanding mosquito metabolism?

Metabolism is a complicated process that involves the entire set of chemical transformations present in an organism. A metabolic challenge faced by mosquitoes is how to break down ammonia that results from digesting a blood meal and is toxic to the mosquito. With NIAID support, we found that in the absence of a functional metabolic cycle to detoxify ammonia, A. aegypti mosquitoes use specific metabolic pathways that were believed to be non-existent in insects. This discovery has opened a new field of study. 

A better understanding of mosquito metabolism and its mechanisms of regulation in A. aegypti and other mosquito species could lead us to the discovery of common and novel metabolic targets and/or metabolic regulators. It would also provide a strong foundation for the development and implementation of more effective biological, chemical and/or genetic strategies to control mosquito populations around the world. 

What are the biggest challenges to studying mosquito metabolism?

We have often observed that genetic silencing or knockdown—a technique to prevent or reduce gene expression—of one or more genes encoding specific proteins involved in mosquito nitrogen metabolism results in a variety of unpredictable phenotypes based on our knowledge of vertebrate nitrogen metabolism. Notably, female mosquitoes get control of the deficiency of certain key proteins by downregulating or upregulating one or multiple metabolic pathways simultaneously and at a very high speed. This highlights the tremendous adaptive capacity of blood-fed mosquitoes to avoid deleterious effects and survive.

We have been collaborating closely with scientists that work at the University of Texas MD Anderson Cancer Center Metabolomics Core Facility, and more recently, with bioanalytical chemists that work in the Microbiome Center’s Metabolomics and Proteomics Mass Spectrometry Laboratory in Texas Children’s Hospital in Houston. Our projects are not turn-key type of projects with quick turn-round times. We have to invest considerable time and effort to successfully develop and/or optimize methods before analyzing mosquito samples. Despite these challenges, our research work keeps motivating us to unlock the metabolic mysteries that female mosquitoes hold.

Your research has focused on Aedes aegypti, the main vector of dengue, Zika, etc.  Why did you choose to study this mosquito species rather than others that are also important vectors of malaria and other diseases?

My research has focused on Aedes aegypti not only because it is a vector of pathogens that pose public health threats, but also because it is genetically one of the best-characterized insect species. The availability of the Aedes aegypti genome is a great resource for a wide range of investigations. In addition, Aedes aegypti is relatively simple to rear and maintain in the lab. In my lab, we are interested in expanding our metabolic studies to other mosquito species by working in collaboration with scientists with expertise in the biology of different vectors.

What important questions remain unanswered about mosquito metabolism?

Many important questions remain unanswered about mosquito metabolism. I’d like to highlight a few of them that may help us enhance our knowledge of the mosquito as a whole organism rather than as a linear sum of its parts. For example, what are the genetic and biochemical mechanisms that drive metabolic fluxes in mosquitoes in response to internal or external alterations? How do key proteins interact with each other, and how are they post-translationally regulated to maintain mosquito metabolism? How are the metabolic networks regulated in noninfected and pathogen-infected mosquitoes? What are the critical regulatory points within the mosquito metabolism and the vector-host-pathogen interface? 

While basic science will continue to be crucial in answering these questions, to successfully fight against mosquitoes, we must work together as part of a multidisciplinary team of scientists to tightly coordinate our efforts and close the gap between basic and applied science. 

Malaria, one of the deadliest infectious diseases on the planet, has had a profound impact on humanity throughout history. This disease has even left its mark in our DNA: Many scientists believe it has had a strong selective pressure on the human genome over time. Because malaria is often fatal in children, babies born with some degree of resistance to the parasite that causes malaria have a better likelihood of growing up and passing those traits along to their own children. Unfortunately, some of these traits may come at a price: For more than 50 years, scientists have documented that malaria infection is associated with high levels of autoantibodies—antibodies that recognize and attack the person’s own tissues and are associated with autoimmune disorders.

To investigate the link between autoantibodies and malaria immunity, NIAID researchers, along with their colleagues, have studied the molecular mechanisms of these malaria defense systems. Their findings, recently published in Immunity, reveal the associations between malaria, human resistance to it, and autoantibodies that are linked to certain autoimmune disorders—specifically, systemic lupus erythematosus (SLE).

The researchers began by examining a collection of blood samples collected during a longitudinal study of 602 people, aged three months to 25 years, in the West African country of Mali. Malaria transmission is highly seasonal in Mali: the parasite which causes malaria, Plasmodium falciparum, is transmitted by mosquitoes, which need certain conditions to reproduce. During the dry season, which ends in May, malaria transmission rates are low. The researchers tested for autoantibodies in blood samples that were collected in May and then linked this with whether the participant had symptomatic malaria that needed treatment during the ensuing malaria season.

Participants who had very high levels of autoantibodies had a 41 percent lower risk of getting sick with malaria than people who had low levels of autoantibodies. To investigate how autoantibodies might protect from malaria, the researchers took blood samples with high levels of autoantibodies and isolated the autoantibodies. They then exposed malaria parasites to the autoantibodies in the laboratory and found that parasite growth was inhibited. The autoantibodies bound to proteins that the parasite uses to invade human red blood cells. The researchers believe that something similar may have happened to the participants of this study—their autoantibodies reduced the parasite’s ability to invade and grow in their blood cells, increasing their chances of remaining free of malaria symptoms.

Although this adaptation seems beneficial, it may come with a catch. Very similar autoantibodies can be found in the blood of people with SLE. This chronic autoimmune disorder can affect almost any organ system, but it often manifests as a rash, joint pain, and persistent fatigue. In its worst forms, it can be debilitating. While the causes of SLE are still unknown, it does appear to have a genetic component—for example, in the U.S., SLE is more common in some ethnic groups than others, including people with African ancestry. However, for unclear reasons, SLE and other autoimmune disorders are less common in Africa, suggesting that other factors alter the immune system to decrease the risk of autoimmune disorders there. Participants in the Mali study with high levels of autoantibodies had no symptoms of SLE or other autoimmune disorders.

When the researchers tested autoantibodies from people in the United States with SLE, they reacted to malaria parasites similar to the autoantibodies from the Malian study participants. These findings suggest that the overactive immune response that contributes to SLE may have evolved to defend against malaria. Even though many people with SLE today will never encounter a malaria-carrying mosquito, they still produce the antibodies that may have helped their ancestors survive malaria.

Reference:

Hagadorn, K et al. Autoantibodies inhibit Plasmodium falciparum growth and are associated with protection from clinical malaria. Immunity. DOI: https://doi.org/10.1016/j.immuni.2024.05.024 (2024)