Genetically Engineered Bacteria Prevent Mosquitoes From Transmitting Malaria

Researchers at the Johns Hopkins Malaria Research Institute have genetically modified a bacterium commonly found in the mosquito’s midgut and found that the parasite that causes malaria in people does not survive in mosquitoes carrying the modified bacterium. The bacterium, Pantoea agglomerans, was modified to secrete proteins toxic to the malaria parasite, but the toxins do not harm the mosquito or humans. According to a study published by PNAS, the modified bacteria were 98 percent effective in reducing the malaria parasite burden in mosquitoes.

“In the past, we worked to genetically modify the mosquito to resist malaria, but genetic modification of bacteria is a simpler approach,” said Marcelo Jacobs-Lorena, PhD, senior author of the study and a professor with Johns Hopkins Bloomberg School of Public Health. “The ultimate goal is to completely prevent the mosquito from spreading the malaria parasite to people.”

With the study, Jacobs-Lorena and his colleagues found that the engineered P. agglomerans strains inhibited development of the deadliest human malaria parasite Plasmodium falciparum and rodent malaria parasite Plasmodium berghei by up to 98 percent within the mosquito. The proportion of mosquitoes carrying parasites (prevalence) decreased by up to 84 percent.

“We demonstrate the use of an engineered symbiotic bacterium to interfere with the development of P. falciparum in the mosquito. These findings provide the foundation for the use of genetically modified symbiotic bacteria as a powerful tool to combat malaria,” said Jacobs-Lorena.

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

The authors of “Fighting malaria with engineered symbiotic bacteria from vector mosquitoes” are Sibao Wang, Anil K. Ghosh, Nicholas Bongio, Kevin A. Stebbings, David J. Lampe and Marcelo Jacobs-Lorena.

The research was supported by National Institute of Allergy and Infectious Diseases, the Bill & Melinda Gates Foundation, the Johns Hopkins Malaria Research Institute and the Bloomberg Family Foundation.

Source: Johns Hopkins Bloomberg School of Public Health

Researchers Discover Proteins in Mosquitoes that Help Fight Malaria Infection

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

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

Contrasting Patterns of Malaria Drug Resistance Found Between Humans and Mosquitoes

A recent study has detected contrasting patterns of drug resistance in malaria-causing parasites taken from both humans and mosquitoes in rural Zambia.

Parasites found in human blood samples showed a high prevalence for pyrimethamine-resistance, which was consistent with the class of drugs widely used to treat malaria in the region. However, parasites taken from mosquitoes themselves had very low prevalence of pyrimethamine-resistance and a high prevalence of cycloguanil-resistant mutants indicating resistance to a newer class of antimalaria drug not widely used in Zambia.

The study was conducted by researchers at the Johns Hopkins Malaria Research Institute and their Zambian colleagues and the findings were published November 7, 2011 in the online edition of the journal PNAS.

Surveillance for drug-resistant parasites in human blood is a major effort in malaria control. Malaria in humans is caused by the parasite Plasmodium falciparum, which is spread from person to person through the feeding of the Anopheles mosquito. Over time, through repeated exposure to medications, the parasites can become less susceptible to drugs used to treat malaria infection, limiting their effectiveness.

“This contrast in resistance factors was a big surprise to us,” said Peter Agre, MD, an author of the study and director of the Johns Hopkins Malaria Institute. “The contrast raises many questions, but we suspect that the malaria parasite can bear highly host-specific drug-resistant polymorphisms, most likely reflecting very different selection preferences between humans and mosquitos.”

For the study, Sungano Mharakurwa, PhD, lead author and senior research associate with the Johns Hopkins Malaria Research Institute in Macha, Zambia, conducted a DNA analysis of P. falciparum found in human blood samples to those found in mosquitoes collected inside homes in rural Zambia. In samples taken from human blood, pyrimethamine-resistant mutations were greater than 90 percent and between 30 percent to 80 percent for other polymorphisms. Mutations of cycloguanil-resistance were 13 percent.

For parasites found in the mosquito midgut, cycloguanil-resistant mutants were at 90 percent while pyrimethamine-resistant mutants were detected between 2 percent and 12 percent.

“Our study indicates that mosquitoes exert an independent selection on drug resistant parasites—a finding that has not previously been noticed. If confirmed in other malaria endemic regions, it suggests an explanation for why drug resistance may appear so rapidly,” said Mharakurwa.

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 “Malaria antifolate resistance with contrasting Plasmodium falciparum dihydrofolate reductase (DHFR) polymorphisms in humans and Anopheles mosquitoes” are Sungano Mharakurwa, Taida Kumwenda, Mtawa A. P. Mkulama, Mulenga Musapa, Sandra Chishimba, Clive J. Shiff, David J. Sullivan, Philip E. Thuma, Kun Liu and Peter Agre.

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.

Funding was provided by the Johns Hopkins Malaria Research Institute, the Bill & Melinda Gates Foundation and the National Institutes of Health.

Source: Johns Hopkins University

Interview with Peter Agre, Johns Hopkins Malaria Research Institute Director

Peter Agre is director of the Johns Hopkins Malaria Research Institute, which celebrates its 10th birthday this year. Before turning his focus to malaria, Agre won the Nobel Prize in Chemistry in 2003 for his discovery of aquaporins, water channels in cell membranes. Agre spends a third of his year in regions of the world where malaria is endemic, mostly in Zimbabwe and rural Zambia, but he has never had the disease.

Rachel Saslow of the Washington Post recently spoke with Agre, 62, about malaria, his scheme to meet actor George Clooney and how he got a D in high school chemistry.

Read the interview, via: The Washington Post.