Microbes That Stop Malaria

“The malaria parasite has been killing children and sapping the strength of whole populations for tens of thousands of years. It is impossible to calculate the harm malaria has done to the world.”

- Bill Gates

“I am continually surprised by Wolbachia.”

- Beth McGaw, professor of entomology, Penn State University

The mosquito is the most lethal animal in the world. According to the World Health Organization (WHO), mosquito bites result in more than one million human deaths every year, malaria being one of the major causes. Unless you live in sub-Saharan Africa, where malaria deaths recently dwarfed COVID-19 fatalities, you have no fear of (or perhaps even knowledge of) Plasmodium falciparum, the parasite that causes most malaria-related deaths. But if SARS-CoV-2 has taught us anything, it is that diseases are global and that what happens in one part of the world may, in one way or another, ultimately affects us all. In this Germ Gem post, I review some key aspects of malaria and highlight new approaches to eliminating the mosquito vector.

Malaria and the Mosquito Vector. The word malaria comes from the Italian words mal, meaning “bad,” and aria, meaning “air.” The ancient Romans blamed the air in swamps for the disease, and they weren’t too far off. Malaria is transmitted by the bite of infected Anopheles mosquitoes, which breed in swamps and other stagnant water.

All mosquitoes have two things in common. First, only the females bite and draw blood, which contains proteins needed by their eggs. Second, all mosquitoes are dependent upon water (where they lay their eggs) and warm temperatures—which accounts for more mosquito species being found in tropical countries. There are 3,500 different species of mosquitoes worldwide. But only 40 species, all members of the genus Anopheles, carry Plasmodium falciparum, the parasite that causes most fatal cases of malaria.

Malaria has wreaked enormous havoc throughout history. It was rife in the Roman Empire. During the U.S. Civil War, more than one million Union soldiers contracted malaria, and roughly 30,000 died from it. In the early part of the Twentieth Century, it was endemic in parts of the Southern United States. In fact, at its inception on July 1, 1946, the mission of the Center for Disease Control and Prevention was focused mainly on the control and elimination of malaria in the United States. Nowadays, about 2,000 cases of malaria are diagnosed in the U.S. each year and the vast majority of these are in travelers and immigrants coming from other countries, mostly sub-Saharan Africa and South Asia, where malaria transmission occurs.

Malaria Is Still a Problem Globally. Since 2000, the rate of malaria infections plunged by 60% worldwide. It has been eliminated in 111 countries, and 34 countries are advancing toward elimination. According to the WHO’s “World Malaria Report 2020: 20 years of global progress and challenges,” since the year 2000, 1.5 billion malaria cases and 7.6 million malaria-related deaths (mainly in children under 5 years old) have been prevented. Former WHO director-general Margaret Chan hailed this as one of the great public health success stories of our millennium.

The remarkable fall in the incidence and mortality of malaria in the early years of this century was due to many improvements in public health, such as the use of pyrethrin-impregnated mosquito bed nets, advanced diagnostic tests, and new treatments, especially the antimalarial drug, artemisinin. But in the past 5 years this progress has leveled off. In 2019, there were 229 million cases of malaria with 409,000 deaths. Resistance of mosquitoes to pyrethrin and of Plasmodium falciparum to artemisinin is mounting. Recognizing these recent trends as a wake-up call, the WHO is “drawing attention not only to the need to innovate against the vector and the parasite—by developing new tools, strategies and problem-solving approaches at the frontline of malaria control—but also to ensure that the global response evolves.” As the current WHO director-general Tedros Adhanom Ghebreyesus exclaimed recently: “It is time for leaders across Africa—and the world—to rise once again to the challenge of malaria, just as they did when they laid the foundation for the progress made since the beginning of this century.”

Much like the realization that winning the battle against SARS-CoV-2 hinged upon development and deployment of a vaccine, so too overcoming Plasmodium falciparum ultimately depends on creating an effective vaccine. Small inroads have been made in this effort, but this challenge has stymied a number of brilliant scientists. Therefore, until this goal is achieved, other strategies need to be developed.

Germ Warfare Strategy. Recently, two innovative approaches to stopping malaria have been reported. Both are aimed at the mosquito vector and involve the use of microbes that stop reproduction of the Plasmodium falciparum parasite in mosquitoes.

The idea that infecting mosquitoes with microbes could interfere with the reproduction of plasmodia can be traced to 1924. That was the year that the pathologists Wolbach and Hertig discovered a gram-negative, obligate intracellular bacterium in mosquito eggs, ultimately named Wolbachia, after Simeon Wolbach. Subsequently, it was determined that roughly 40% of all terrestrial insect species harbor this bacterium, making Wolbachia the most prevalent bacterial symbiont on the planet. (Like pathogens, symbionts live inside the body, but they are helpful rather than harmful.) Spiders, flies, ants, beetles, and worms are also hosts for Wolbachia, but the bacterium has no interest in mammals, including Homo sapiens. Arguably, Wolbachia is the most successful bacterium in the world, and one of its most amazing tricks is that it is a master manipulator of the sex life of its insect hosts—it both feminizes and kills off males.

The potential impact of using Wolbachia-infected mosquitoes to control a devastating tropical disease is already being demonstrated with another mosquito species, Aedes aegypti, the vector of the virus that causes dengue fever. (The WHO estimates that 50-100 million cases of dengue occur annually with at least 22,000 deaths per year.) In an article by Ewen Callaway in Nature News in August 2020 entitled “The mosquito strategy that could eliminate dengue,” a field trial in Indonesia showed that releasing mosquitoes modified to carry Wolbachia resulted in a 77% reduction in cases of dengue over a several year period. The results of this study were heralded as “extraordinary” and “a real breakthrough.”

While the evidence that using Wolbachia-infected Aedes aegypti mosquitoes to control dengue is generating great excitement around the world—including in Miami-Dade County where a Wolbachia-infected mosquito control program recently demonstrated extremely positive results—this strategy has been slow to catch on in controlling malaria. This is because Anopheles mosquitoes were long considered inhospitable for Wolbachia. The recent discovery, however, of natural Wolbachia infection in Anopheles arabiensis in Tanzania, reported in December 2018 has awakened interest in developing Wolbachia-infected Anopheles mosquitoes to stop malaria.

In May 2020, a second kind of microbe—a microsporidium—was reported to impair Plasmodium falciparum transmission in Anopheles mosquitoes. Microsporidia are a group of spore-forming microorganisms that were once considered protozoans or protists but are now known to be fungi. Roughly 1,500 of the more than one million species are named. Most of them infect insects, but many species infect vertebrates, including humans, in whom they can cause the disease microsporidiosis (an intestinal infection found in immunocompromised hosts such as HIV/AIDS patients).

Microsporidium MB, recently discovered in Kenya, is the species that has generated much enthusiasm. In the May 2020 issue of the journal Nature Communications, scientists reported that Microsporidium MB completely blocked Plasmodium falciparum transmission in Anopheles arabiensis mosquitoes. They are now working on understanding not only how Microsporidium MB is spread but also on determining the mechanism by which it prevents malaria. The good news, however, is that as Microsporidium MB does not kill the mosquitoes, it would not have an adverse impact on ecosystems that are dependent upon mosquitoes as food.

What about the ‘Insect Apocalypse’? A fundamental tenet of ecology is that all animal, plant, and microbial life, as well as inanimate components of the environment are connected. Interfering with any one of these elements can impact others. Insects are the most ubiquitous and diverse animals on the planet to which they contribute multiple critical ecosystem services. Thus man-made depletions of mosquito populations, such as, Anopheles and Aedes, the vectors for malaria and dengue (as well as several other serious viral diseases), respectively, could have unforeseen consequences.

You may have read about the drastic declines in insect abundance across the board (not just monarch butterflies and honeybees). In her 2018 New York Times article, “The Insect Apocalypse Is Here: What does it mean for the rest of life on Earth?,” journalist Brook Jarvis wrote: “[B]ugs are the wildlife we know best, the nondomesticated animals whose lives intersect most intimately with our own . . . In another sense, though, they are one of our planet’s greatest mysteries, a reminder of how little we know about what’s happening in the world around us.”

In a 2020 article in Science, the German ecologist Roel van Klink and his associates reported: “Meta-analysis reveals declines in terrestrial but increases in freshwater insect abundances.” These findings are more reassuring and show that determining the fate of insects is very complicated.

No one wants an insect apocalypse to occur. Therefore it is extremely important to monitor closely the effects of all measures used to eradicate mosquitoes. Nonetheless, it is my opinion that people living in sub-Saharan Africa would be well-served by the elimination of as many Plasmodium falciparum-bearing mosquitoes as possible. The same could be said for large areas of the world that are plagued by mosquitoes that carry dengue virus and other life-threatening human pathogens.