Malaria Infected Mosquitoes Attracted to Human Odor

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Abstract

There is much evidence that some pathogens manipulate the behaviour of their mosquito hosts to enhance pathogen transmission. However, it is unknown whether this phenomenon exists in the interaction of Anopheles gambiae sensu stricto with the malaria parasite, Plasmodium falciparum – one of the most important interactions in the context of humanity, with malaria causing over 200 million human cases and over 770 thousand deaths each year.

Here we demonstrate, for the first time, that infection with P. falciparum causes alterations in behavioural responses to host-derived olfactory stimuli in host-seeking female An. gambiae s.s. mosquitoes. In behavioural experiments we showed that P. falciparum-infected An. gambiae mosquitoes were significantly more attracted to human odors than uninfected mosquitoes. Both P. falciparum-infected and uninfected mosquitoes landed significantly more on a substrate emanating human skin odor compared to a clean substrate. However, significantly more infected mosquitoes landed and probed on a substrate emanating human skin odor than uninfected mosquitoes. [Read more…]

How Mosquito Immune System Attacks Specific Infections, Including Malaria Parasite

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Researchers have determined a new mechanism by which the mosquitoes’ immune system can respond with specificity to infections with various pathogens, including the parasite that causes malaria in humans, using one single gene.

Unlike humans and other animals, insects do not make antibodies to target specific infections. According to researchers at the Johns Hopkins Bloomberg School of Public Health, mosquitoes use a mechanism known as alternative splicing to arrange different combinations of binding domains, encoded by the same AgDscam gene, into protein repertoires that are specific for different invading pathogens. The researchers’ findings were published October 18 in the journal Cell Host & Microbe and could lead to new ways to prevent the spread of a variety of mosquito born illnesses.

Mosquitoes and other insects use their primitive innate immune systems to successfully fight infections with a broad spectrum of viruses, bacteria, fungi and parasites, despite the lack of antibodies that are part of the more sophisticated human immune system. The effectiveness of the human immune system is to a large degree based on the ability to produce an enormous variety of antibodies containing different immunoglobulin domains that can specifically tag and label a pathogen for destruction. This great variety of pathogen-binding antibodies is achieved by combining different immunoglobulin gene segments and further mutate them through mechanisms called somatic recombination and hypermutation. While mosquitoes also have genes encoding immunoglobulin domains, they lack these specific mechanisms to achieve pathogen recognition diversity.

The Johns Hopkins researchers discovered a different way by which mosquitoes can combine immunoglobulin domains of a single gene called AgDscam (Anopheles gambiae Down Syndrome Cell Adhesion Molecule) to produce a variety of pathogen-binding proteins. The AgDscam gene is subjected to a mechanism called alternative splicing that combines different immunoglobulin domains into mature AgDscam proteins, depending on which pathogen has infected the mosquito. The researchers showed that this alternative splicing is guided by the immune signal transducing pathways (analogous to electrical circuits) that they previously demonstrated to activate defenses against different malaria parasites and other pathogens. While alternative splicing of the AgDscam gene does not nearly achieve the degree of pathogen recognition diversity of human antibodies, it does nevertheless vastly increase the variety of pathogen binding molecules.

“Using antibodies to fight infection is like fishing with a harpoon—it’s very targeted. The mosquito’s innate immune system is more like fishing with a net—it catches a bit of everything,” explained George Dimopoulos, PhD, senior investigator of the study and professor with the Johns Hopkins Malaria Research Institute. “However, we discovered that immune pathway-guided alternative splicing of the AgDscam gene renders the mosquito’s immune net, so to speak, more specific than previously suspected. The mosquito’s immune system can come up with approximately 32,000 AgDscam protein combinations to target infections with greater specificity.”

Dimopoulos and his group are developing a malaria control strategy based on mosquitoes that have been genetically modified to possess an enhanced immune defense against the malaria parasite Plasmodium. One obstacle to this approach is the great variety of Plasmodium strains that may interact somewhat differently with the mosquito’s immune system.

“Some of these strains may not be detected by the engineered immune system proteins that mediate their killing. Our new discovery may provide the means to create genetically modified mosquitoes that can target a broader variety of parasite strains, like casting a net rather than shooting with a harpoon,” said Dimopoulos.

Malaria kills more than 800,000 people worldwide each year. Many are children.

“Anopheles NF-kB –Regulated Splicing Factors Direct Pathogen-Specific Repertoires of the Hypervariable Pattern Recognition Receptor AgDscam” was written by Yuemei Dong, Chris M. Cirimotich, Andrew Pike, Ramesh Chandra and George Dimopoulos.

The research was supported by grants from the National Institutes of Health/National Institute of Allergy and Infectious Disease, the Calvin A. and Helen H. Lang Fellowship, and the Johns Hopkins Malaria Research Institute.

Sources: Johns Hopkins Bloomberg School of Public Health; Cell Host & Microbe

Researchers Discover Proteins in Mosquitoes that Help Fight Malaria Infection

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Researchers have discovered the function of a series proteins within the mosquito that transduce a signal that enables the mosquito to fight off infection from the parasite that causes malaria in humans. Together, these proteins are known as immune deficiency (Imd) pathway signal transducing factors, are analogous to an electrical circuit. As each factor is switched on or off it triggers or inhibits the next, finally leading to the launch of an immune response against the malaria parasite.

The latest study, conducted at the Johns Hopkins Malaria Research Institute, builds upon earlier work of the research team, in which they found that silencing one gene of this circuit, Caspar, activated Rel2, an Imd pathway transcription factor of the Anopheles gambiae mosquito. The activation of Rel2 turns on the effectors TEP1, APL1 and FBN9 that kill malaria-causing parasites in the mosquito’s gut. More significantly, this study discovered the Imd pathway signal transducing factors and effectors that will mediate a successful reduction of parasite infection at their early ookinete stage, as well as in the later oocyst stage when the levels of infection were similar to those found in nature.

“Identifying and understanding how all of the players work is crucial for manipulating the Imd pathway as an invention to control malaria. We now know which genes can be manipulated through genetic engineering to create a malaria resistant mosquito” said George Dimopoulos PhD, professor in the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health.

To conduct the study, Dimopoulos’s team used a RNA interference method to “knock down” the genes of the Imd pathway. As the components were inactivated, the researchers could observe how the mosquito’s resistance to parasite infection would change.

“Imagine a string of Christmas lights or other circuit that will not work when parts aren’t aligned in the right sequence. That is how we are working with the mosquito’s immune system,” explained Dimopolous. “We manipulate the molecular components of the mosquito’s immune system to identify the parts necessary to kill the malaria parasites.”

Malaria kills more than 800,000 people worldwide each year. Many are children.

The authors of “Anopheles Imd pathway factors and effectors in infection intensity-dependent anti-Plasmodium action” are Lindsey S. Garver, Ana C. Bahia, Suchismita Das, Jayme A. Souza-Neo, Jessica Shiao, Yuemei Dong and George Dimopoulos.

The research was funded by the Johns Hopkins Malaria Research Institute and was published June 7, 2012 in the journal PLoS Pathogens.

Source: Johns Hopkins Bloomberg School of Public Health

Mosquito Immune System Can Be Engineered to Block Malaria

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Researchers have demonstrated for the first time that the Anopheles mosquito’s innate immune system could be genetically engineered to block the transmission of the malaria-causing parasite to humans. In addition, they showed that the genetic modification had little impact on the mosquito’s fitness under laboratory conditions.

“The immune system of the Anopheles mosquito is capable of killing a large proportion—but not all—of the disease-causing parasites that are ingested when the mosquito feeds on an infected human,” said George Dimopoulos, PhD, senior author of the study and associate professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. “We’ve genetically engineered this immune system to create mosquitoes that are better at blocking the transmission of the human malaria parasite Plasmodium falciparum. ”

For the study, Dimopoulos and his team genetically engineered Anopheles mosquitoes to produce higher than normal levels of an immune system protein Rel2 when they feed on blood. Rel2 acts against the malaria parasite in the mosquito by launching an immune attack involving a variety of anti-parasitic molecules. Through this approach, instead of introducing a new gene into the mosquito DNA, the researchers used one of the insect’s own genes to strengthen its parasite-fighting capabilities. According to the researchers, this type of genetically modified mosquito could be further developed and used to convert malaria-transmitting to Plasmodium-resistant mosquito populations. One possible obstacle for this approach is the fitness of the genetically modified malaria resistant mosquitoes, since they would have to compete with the natural malaria-transmitting mosquitoes. The researchers showed with their study that the Rel2 genetically modified mosquito strain lived as long, and laid as many eggs, as the non-modified wild type mosquitoes, thereby suggesting that their fitness had not become significantly impaired.

“Malaria is one of world’s most serious public health problems. Mosquitoes and the malaria parasite are becoming more resistant to insecticides and drugs, and new control methods are urgently needed. We’ve taken a giant step towards the development of new mosquito strains that could be released to limit malaria transmission, but further studies are needed to render this approach safe and fail-proof,” said Dimopoulos.
Worldwide, malaria afflicts more than 225 million people. Each year, the disease kills approximately 800,000, many of whom are children living in Africa.

Authors of “Engineered Anopheles immunity to Plasmodium infection” are Yuemei Dong, Suchismita Das, Chris Cirimotich, Jayme A. Souza-Neto, Kyle J. McLean and George Dimopoulos.

The Johns Hopkins Malaria Research Institute is a state-of-the-art research facility at the Johns Hopkins Bloomberg School of Public Health. It focuses on a broad program of basic science research to treat and control malaria, develop a vaccine and find new drug targets to prevent and cure this deadly disease.

The researchers’ findings were published December 22, 2011 in the online journal PLoS Pathogens. Funding was provided by the National Institutes of Health and the Johns Hopkins Malaria Research Institute.

 

Source: Johns Hopkins Bloomberg School of Public Health

Researchers Discover Microbe That Could Help Fight Malaria

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Researchers have discovered a bacterium in the gut of the Anopheles mosquito which may someday be used to destroy and, therefore, prevent the spread of the disease-causing parasite.

The World Health Organization estimates 800,000 people die of malaria each year. The parasite that causes the disease is transmitted by the Anopheles mosquito. After the mosquito feeds on the blood of an infected individual, the parasite matures into an infectious stage in the insect’s gut.  From there, the parasite, known as Plasmodium falciparum, takes up residence in the mosquito’s salivary glands so it can infect the next person that’s bitten.

Researchers at Johns Hopkins School of Public Health in Baltimore, Maryland found the bacterium in the gut of the Anopheles mosquito among hundreds of so-called microbial flora that live harmlessly in the stomach of a group of Anopheles mosquitoes collected in an area of southern Zambia where malaria is rampant.

The microbe, which was in the guts of a small percentage of the mosquitoes, protected those insects against infection with the parasite.

Lead researcher George Dimopoulos says the protection seems to be a side-effect of the bacterium’s normal bodily function, adding that scientists would like to figure out a way to use the microbe as a weapon against malaria.

“Our study has shown that this bacterium produces free radicals, molecules that contain oxygen and that can cause damage to cells.  So, we believe that’s how this bacterium is killing the malaria parasite in the mosquito gut.  But we need to understand that mechanism in greater detail.”

To demonstrate the beneficial effect, the researchers used antibiotics to kill the bacterium in mosquitoes that contained it, and were then able to infect those mosquitoes more easily with the Plasmodium parasite.

They also introduced the bacterium into the guts of mosquitoes that didn’t have it. When they fed this group infected blood, the parasite was destroyed in nearly all of the insects.

Dimopoulos says researchers’ goal now is to figure out a way to introduce the microbe into large populations of Anopheles mosquitoes – perhaps through bait laced with their favorite snack.

“Mosquitoes need to feed on sugar every day.  And one can potentially expose mosquitoes in the field to these bacteria through sugar bait.”

The researchers noted that mosquitoes with the bacterium in their guts die sooner than those without it – when both groups are infected with the parasite. Since the malaria parasite lives in mosquitoes for about two weeks before maturing to an infectious stage, Dimopoulos says it’s good news that the stomach bacterium seems to shorten the insect’s lifespan, before it could potentially transmit the parasite to humans.

Source: VOA News