Johns Hopkins Malaria Research Institute

Baltimore, MD, United States

Johns Hopkins Malaria Research Institute

Baltimore, MD, United States
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Liu K.,Johns Hopkins Malaria Research Institute | Tsujimoto H.,Johns Hopkins Malaria Research Institute | Cha S.-J.,Johns Hopkins Malaria Research Institute | Agre P.,Johns Hopkins Malaria Research Institute | Rasgon J.L.,Johns Hopkins Malaria Research Institute
Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

Altered patterns of malaria endemicity reflect, in part, changes in feeding behavior and climate adaptation of mosquito vectors. Aquaporin (AQP) water channels are found throughout nature and confer high-capacity water flow through cell membranes. The genome of the major malaria vector mosquito Anopheles gambiae contains at least seven putative AQP sequences. Anticipating that transmembrane water movements are important during the life cycle of A. gambiae, we identified and characterized the A. gambiae aquaporin 1 (AgAQP1) protein that is homologous to AQPs known in humans, Drosophila, and sap-sucking insects. When expressed in Xenopus laevis oocytes, AgAQP1 transports water but not glycerol. Similar to mammalian AQPs, water permeation of AgAQP1 is inhibited by HgCl2 and tetraethylammonium, with Tyr185 conferring tetraethylammonium sensitivity. AgAQP1 is more highly expressed in adult female A. gambiae mosquitoes than in males. Expression is high in gut, ovaries, and Malpighian tubules where immunofluorescence microscopy reveals that AgAQP1 resides in stellate cells but not principal cells. AgAQP1 expression is up-regulated in fat body and ovary by blood feeding but not by sugar feeding, and it is reduced by exposure to a dehydrating environment (42% relative humidity). RNA interference reduces AgAQP1 mRNA and protein levels. In a desiccating environment (<20% relative humidity), mosquitoes with reduced AgAQP1 protein survive significantly longer than controls. These studies support a role for AgAQP1 in water homeostasis during blood feeding and humidity adaptation of A. gambiae, a major mosquito vector of human malaria in sub-Saharan Africa.


News Article | November 17, 2016
Site: www.biosciencetechnology.com

Researchers at MIT and Brigham and Women’s Hospital have developed a new drug capsule that remains in the stomach for up to two weeks after being swallowed, gradually releasing its drug payload. This type of drug delivery could replace inconvenient regimens that require repeated doses, which would help to overcome one of the major obstacles to treating and potentially eliminating diseases such as malaria. In a study described in the Nov. 16 issue of Science Translational Medicine, the researchers used this approach to deliver a drug called ivermectin, which they believe could aid in malaria elimination efforts. However, this approach could be applicable to many other diseases, said Robert Langer, the David H. Koch Institute Professor at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research. “Until now, oral drugs would almost never last for more than a day,” Langer said. “This really opens the door to ultra-long-lasting oral systems, which could have an effect on all kinds of diseases, such as Alzheimer’s or mental health disorders. There are a lot of exciting things this could someday enable.” Langer and Giovanni Traverso, a research affiliate at the Koch Institute and a gastroenterologist and biomedical engineer at Brigham and Women’s Hospital, are the senior authors of the paper. The paper’s lead authors are former MIT postdoc Andrew Bellinger, MIT postdoc Mousa Jafari, and former MIT postdocs Tyler Grant and Shiyi Zhang. The team also includes researchers from Harvard University, Imperial College London, and the Institute for Disease Modeling in Bellevue, Washington. The research has led to the launching of Lyndra, a Cambridge-based company that is developing the technology with a focus on diseases for which patients would benefit the most from sustained drug delivery, including neuropsychiatric disorders, HIV, diabetes, and epilepsy. Drugs taken orally tend to work for a limited time because they pass rapidly through the body and are exposed to harsh environments in the stomach and intestines. Langer’s lab has been working for several years to overcome this challenge, with an initial focus on malaria and ivermectin, which kills any mosquito that bites a person who is taking the drug. This can greatly reduce the transmission of malaria and other mosquito-borne illnesses. The team envisions that long-term delivery of ivermectin could help with malaria elimination campaigns based on mass drug administration — the treatment of an entire population, whether infected or not, in an area where a disease is common. In this scenario, ivermectin would be paired with the antimalaria drug artemisinin. “Getting patients to take medicine day after day after day is really challenging,” said Bellinger, now a cardiologist at Brigham and Women’s Hospital and chief scientific officer at Lyndra. “If the medicine could be effective for a long period of time, you could radically improve the efficacy of your mass drug administration campaigns.” To achieve ultra-long-term delivery, drugs need to be packaged in a capsule that is stable enough to survive the harsh environment of the stomach and can release its contents over time. Once the drug is released, the capsule must break down and pass safely through the digestive tract. Working with those criteria in mind, the team designed a star-shaped structure with six arms that can be folded inward and encased in a smooth capsule. Drug molecules are loaded into the arms, which are made of a rigid polymer called polycaprolactone. Each arm is attached to a rubber-like core by a linker that is designed to eventually break down. After the capsule is swallowed, acid in the stomach dissolves the outer layer of the capsule, allowing the six arms to unfold. Once the star expands, it is large enough to stay in the stomach and resist the forces that would normally push an object further down the digestive tract. However, it is not large enough to cause any harmful blockage of the digestive tract. “When the star opens up inside the stomach, it stays inside the stomach for the duration that you need,” said Grant, now a product development engineer at Lyndra. In tests in pigs, the researchers confirmed that the drug is gradually released over two weeks. The linkers that join the arms to the core then dissolve, allowing the arms to break off. The pieces are small enough that they can pass harmlessly through the digestive tract. “This is a platform into which you can incorporate any drug,” Jafari said. “This can be used with any drug that requires frequent dosing. We can replace that dosing with a single administration.” This type of delivery could also help doctors to run better clinical trials by making it easier for patients to take the drugs, Zhang said. “It may help doctors and the pharma industry to better evaluate the efficacy of certain drugs, because currently a lot of patients in clinical trials have serious medication adherence problems that will mislead the clinical studies,” he said. The new study includes mathematical modeling done by researchers at Imperial College London and the Institute for Disease Modeling to predict the potential impact of this approach. The models suggest that if this technology were used to deliver ivermectin along with antimalaria treatments to 70 percent of a population in a mass drug administration campaign, disease transmission could be reduced the same amount as if 90 percent were treated with antimalaria treatments alone. “What we showed is that we stand to significantly amplify the effect of those campaigns,” Traverso said. “The introduction of this kind of system could have a substantial impact on the fight against malaria and transform clinical care in general by ensuring patients receive their medication.” Peter Agre, director of the Johns Hopkins Malaria Research Institute, who was not involved in the research, described the new approach as a “remarkable” advance that could improve treatment of malaria and any other disease that requires long-term treatment. “If you could reduce the frequency of dosing, and one treatment would continue to release medicine until the course is completed, that would be very beneficial,” Agre said. Researchers led by Traverso are working on developing similar capsules to deliver drugs against other tropical diseases, as well as HIV and tuberculosis. The research was funded by the Bill and Melinda Gates Foundation, the National Institutes of Health, and the Max Planck Research Award.


News Article | November 17, 2016
Site: phys.org

In a study described in the Nov. 16 issue of Science Translational Medicine, the researchers used this approach to deliver a drug called ivermectin, which they believe could aid in malaria elimination efforts. However, this approach could be applicable to many other diseases, says Robert Langer, the David H. Koch Institute Professor at MIT and a member of MIT's Koch Institute for Integrative Cancer Research. "Until now, oral drugs would almost never last for more than a day," Langer says. "This really opens the door to ultra-long-lasting oral systems, which could have an effect on all kinds of diseases, such as Alzheimer's or mental health disorders. There are a lot of exciting things this could someday enable." Langer and Giovanni Traverso, a research affiliate at the Koch Institute and a gastroenterologist and biomedical engineer at Brigham and Women's Hospital, are the senior authors of the paper. The paper's lead authors are former MIT postdoc Andrew Bellinger, MIT postdoc Mousa Jafari, and former MIT postdocs Tyler Grant and Shiyi Zhang. The team also includes researchers from Harvard University, Imperial College London, and the Institute for Disease Modeling in Bellevue, Washington. The research has led to the launching of Lyndra, a Cambridge-based company that is developing the technology with a focus on diseases for which patients would benefit the most from sustained drug delivery, including neuropsychiatric disorders, HIV, diabetes, and epilepsy. Drugs taken orally tend to work for a limited time because they pass rapidly through the body and are exposed to harsh environments in the stomach and intestines. Langer's lab has been working for several years to overcome this challenge, with an initial focus on malaria and ivermectin, which kills any mosquito that bites a person who is taking the drug. This can greatly reduce the transmission of malaria and other mosquito-borne illnesses. The team envisions that long-term delivery of ivermectin could help with malaria elimination campaigns based on mass drug administration—the treatment of an entire population, whether infected or not, in an area where a disease is common. In this scenario, ivermectin would be paired with the antimalaria drug artemisinin. "Getting patients to take medicine day after day after day is really challenging," says Bellinger, now a cardiologist at Brigham and Women's Hospital and chief scientific officer at Lyndra. "If the medicine could be effective for a long period of time, you could radically improve the efficacy of your mass drug administration campaigns." To achieve ultra-long-term delivery, drugs need to be packaged in a capsule that is stable enough to survive the harsh environment of the stomach and can release its contents over time. Once the drug is released, the capsule must break down and pass safely through the digestive tract. Working with those criteria in mind, the team designed a star-shaped structure with six arms that can be folded inward and encased in a smooth capsule. Drug molecules are loaded into the arms, which are made of a rigid polymer called polycaprolactone. Each arm is attached to a rubber-like core by a linker that is designed to eventually break down. After the capsule is swallowed, acid in the stomach dissolves the outer layer of the capsule, allowing the six arms to unfold. Once the star expands, it is large enough to stay in the stomach and resist the forces that would normally push an object further down the digestive tract. However, it is not large enough to cause any harmful blockage of the digestive tract. "When the star opens up inside the stomach, it stays inside the stomach for the duration that you need," says Grant, now a product development engineer at Lyndra. In tests in pigs, the researchers confirmed that the drug is gradually released over two weeks. The linkers that join the arms to the core then dissolve, allowing the arms to break off. The pieces are small enough that they can pass harmlessly through the digestive tract. "This is a platform into which you can incorporate any drug," Jafari says. "This can be used with any drug that requires frequent dosing. We can replace that dosing with a single administration." This type of delivery could also help doctors to run better clinical trials by making it easier for patients to take the drugs, Zhang says. "It may help doctors and the pharma industry to better evaluate the efficacy of certain drugs, because currently a lot of patients in clinical trials have serious medication adherence problems that will mislead the clinical studies," he says. The new study includes mathematical modeling done by researchers at Imperial College London and the Institute for Disease Modeling to predict the potential impact of this approach. The models suggest that if this technology were used to deliver ivermectin along with antimalaria treatments to 70 percent of a population in a mass drug administration campaign, disease transmission could be reduced the same amount as if 90 percent were treated with antimalaria treatments alone. "What we showed is that we stand to significantly amplify the effect of those campaigns," Traverso says. "The introduction of this kind of system could have a substantial impact on the fight against malaria and transform clinical care in general by ensuring patients receive their medication." Peter Agre, director of the Johns Hopkins Malaria Research Institute, who was not involved in the research, described the new approach as a "remarkable" advance that could improve treatment of malaria and any other disease that requires long-term treatment. "If you could reduce the frequency of dosing, and one treatment would continue to release medicine until the course is completed, that would be very beneficial," Agre says. Researchers led by Traverso are working on developing similar capsules to deliver drugs against other tropical diseases, as well as HIV and tuberculosis. Explore further: Ultra-long acting pill offers new hope in eliminating malaria More information: Bellinger AM et al. "Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals." Science Translational Medicine DOI: 10.1126/scitranslmed.aag2374


Douglas R.G.,University of Heidelberg | Amino R.,Institute Pasteur Paris | Sinnis P.,Johns Hopkins Malaria Research Institute | Frischknecht F.,University of Heidelberg
Trends in Parasitology | Year: 2015

Malaria parasites undergo a complex life cycle between their hosts and vectors. During this cycle the parasites invade different types of cells, migrate across barriers, and transfer from one host to another. Recent literature hints at a misunderstanding of the difference between active, parasite-driven migration and passive, circulation-driven movement of the parasite or parasite-infected cells in the various bodily fluids of mosquito and mammalian hosts. Because both active migration and passive transport could be targeted in different ways to interfere with the parasite, a distinction between the two ways the parasite uses to get from one location to another is essential. We discuss the two types of motion needed for parasite dissemination and elaborate on how they could be targeted by future vaccines or drugs. © 2015 Elsevier Ltd.


News Article | April 13, 2016
Site: motherboard.vice.com

As the Zika virus continues to spread through the Americas, researchers have been scrambling to develop a vaccine—an achievement some say we could reach within the year. That’s exciting news, but it raises a question. Why is it we’re able to whip up a vaccine for one mosquito-carried infection in just a few months but we still have no vaccine for one of the deadliest mosquito-borne illnesses on the planet: malaria? Malaria kills over half a million people a year and causes as many as hundreds of millions of cases of infection annually, many of them children. It’s an old disease that has been killing humans since Ancient Egypt, so we’ve had a lot of time to study, understand, and (theoretically) eliminate it. But one of our best hopes for curbing the spread of malaria—vaccination—has eluded us. Why have we been able to develop vaccines for other mosquito-borne illnesses like Japanese encephalitis, yellow fever, and maybe soon dengue and Zika, but not malaria? Unlike many mosquito-borne diseases, malaria is not caused by a virus, but a parasite. Though we’ve got a lot of vaccines for bacterial and viral infections, we don’t have any vaccines for human parasitic infections. That’s because it’s just a lot harder to do, according to Dr. Fidel Zavala, a microbiology and immunology professor at the Johns Hopkins Malaria Research Institute. “Influenza, for example, has something like eight genes. Eight. And malaria has about 5,000 genes,” Zavala told me over the phone. “We’re talking about a completely different level of biological complexity.” With malaria in particular, it gets even more complicated because the parasite matures and changes throughout the infection. At each stage, the parasite produces a different kind of antigen—the molecule that can stimulate an immune response—so by the time the body has recognized it, it’s changed. There are also five different kinds of parasites that can cause malaria, and different populations of these parasites can produce unique antigens, making it a moving target for developing a vaccine. “People can get malaria and the next year get another infection,” said Jun Li, a malaria researcher at the University of Oklahoma. “So even the natural malaria infection cannot stimulate an immune response strong enough to provide full protection against a future infection.” That said, individuals who live in malaria-endemic areas and have survived multiple malaria infections do eventually build up a natural immunity over time, Zavala said. They may still get infections, but it becomes much milder, and often these people are asymptomatic even if they do get malaria. With enough exposure, our body can do naturally what we haven’t yet been able to do in a lab: create an immunity. The trouble is, many people never reach that point, and those that do have to suffer immensely throughout the years. Still, Zavala said this is a signal that a vaccine is possible. And we’ve had some success in the past. In the 1960s and 70s, researchers showed that having people bit by mosquitoes that carried an attenuated version of the malaria parasite effectively vaccinated them—similar to how vaccines like the flu shot work. But this technique was considered too impractical, since you needed mosquitoes to do the inoculation. In more recent years, scientists have developed malaria vaccines that target specific antigens produced by the parasite. These vaccines are partially effective, but not at the rates that get financial donors excited. For one vaccine candidate, which has shown to be about 30 percent effective in infants, the efficacy waned after a few years, leading the World Health Organization to not recommend going forward with it. In a paper published in PLOS Medicine Tuesday, the researchers argued that though not perfect, the vaccine could still save lives, especially for vulnerable newborns. Zavala told me another challenge is that there are few researchers working in this field, and those in it don’t have enough financial backing to make a malaria vaccine a reality. Non-profit organizations like the Gates Foundation invest in this kind of research, but he said there’s still a funding gap. “The evidence has been with us for 40 years, there is simply not a sufficient effort,” he said. “For us, it’s so clear that a vaccine is entirely possible. It’s just a matter of doing the work, but we can’t do it because we are too few, and there is not sufficient financial support.” Correction: An earlier version of this story said malaria kills 1 million people annually. While that used to be true, in recent years the number has dropped to about half a million.


Slack R.D.,Johns Hopkins University | Jacobine A.M.,Johns Hopkins University | Posner G.H.,Johns Hopkins University | Posner G.H.,Johns Hopkins Malaria Research Institute
MedChemComm | Year: 2012

Cyclic peroxides such as the plant-derived 1,2,4-trioxane artemisinin and its derivatives are short-lived, rapidly-acting antimalarials that are now usually combined with standard long-lived, alkaloidal antimalarials; such artemisinin combination therapy (ACT) is the worldwide standard operating procedure for malaria chemotherapy. This review discusses antimalarial monomeric and dimeric derivatives of artemisinin, peroxides not derived from artemisinin, and finally hybrids containing one peroxide unit covalently linked to a non-peroxide unit. Emphasis is placed on the antimalarial effectiveness of these diverse cyclic peroxides and on the simplicity of their synthesis. © 2012 The Royal Society of Chemistry.


Venkatesan M.,Johns Hopkins University | Venkatesan M.,Howard Hughes Medical Institute | Rasgon J.L.,Johns Hopkins University | Rasgon J.L.,Johns Hopkins Malaria Research Institute
Molecular Ecology | Year: 2010

After introduction, West Nile virus (WNV) spread rapidly across the western United States between the years 2001 and 2004. This westward movement is thought to have been mediated by random dispersive movements of resident birds. Little attention has been placed on the role of mosquito vectors in virus dispersal across North America. The mosquito vector largely responsible for WNV amplification and transmission of WNV in the western USA is Culex tarsalis. Here we present population genetic data that suggest a potential role for C. tarsalis in the dispersal of WNV across the western USA. Population genetic structure across the species range of C. tarsalis in the USA was characterized in 16 states using 12 microsatellite loci. structure and geneland analyses indicated the presence of three broad population clusters. Barriers to gene flow were resolved near the Sonoran desert in southern Arizona and between the eastern Rocky Mountains and High Plains plateau. Small genetic distances among populations within clusters indicated that gene flow was not obstructed over large portions of the West Coast and within the Great Plains region. Overall, gene flow in C. tarsalis appears to be extensive, potentially mediated by movement of mosquitoes among neighbouring populations and hindered in geographically limited parts of its range. The pattern of genetic clustering in C. tarsalis is congruent with the pattern of invasion of WNV across the western United States, raising the possibility that movement of this important vector may be involved in viral dispersal. © 2010 Blackwell Publishing Ltd.


Norris L.C.,Johns Hopkins Malaria Research Institute | Norris D.E.,Johns Hopkins Malaria Research Institute
American Journal of Tropical Medicine and Hygiene | Year: 2013

In 2007, the first free mass distribution of insecticide-treated bed nets (ITNs) occurred in southern Zambia. To determine the effect of ITNs on heterogeneity in biting rates, human DNA from Anopheles arabiensis blood meals was genotyped to determine the number of hosts that had contributed to the blood meals. The multiple feeding rate decreased from 18.9% pre-ITN to 9.1% post-ITN, suggesting that mosquito biting had focused onto a smaller fraction of the population. Pre-ITN, 20% of persons in a household provided 40% of blood meals, which increased to 59% post-ITN. To measure heterogeneity over a larger scale, mosquitoes were collected in 90 households in two village areas. Of these households, 25% contributed 78.1% of An. arabiensis, and households with high frequencies of An. arabiensis were significantly spatially clustered. The results indicate that substantial heterogeneity in malaria risk exists at local and household levels, and household-level heterogeneity may be influenced by interventions, such as ITNs. Copyright © 2013 by The American Society of Tropical Medicine and Hygiene.


Rasgon J.L.,Johns Hopkins Malaria Research Institute
Future microbiology | Year: 2011

EVALUATION OF: Fang W, Vega-Rodríguez J, Ghosh AK et al. Development of transgenic fungi that kill human malaria parasites in mosquitoes. Science 331(6020), 1074-1077 (2011). Paratransgenesis is the genetic manipulation of insect endosymbiotic microorganisms such as bacteria, viruses or fungi. Paratransgenesis has been proposed as a potential method to control vector-borne diseases such as malaria. In this article, Fang and colleagues have used genetic manipulation to insert multiple antimalaria effector genes into the entomopathogenic fungus Metarhizium anisopliae. When the modified fungus was used to infect Anopheles mosquitoes, it expressed the antimalaria effector molecules in the mosquito hemolymph. When several different effector molecules were coexpressed, malaria levels in the mosquito salivary glands were inhibited by up to 98% compared with controls. Significant inhibition could be initiated by as little as seven fungal spores and was very rapid and long lasting. These data suggest that recombinant entomopathogenic fungi could be deployed as part of a strategy to control malaria.


Cockburn I.A.,Johns Hopkins Malaria Research Institute | Cockburn I.A.,Australian National University | Tse S.-W.,Johns Hopkins Malaria Research Institute | Tse S.-W.,Harvard University | Zavala F.,Johns Hopkins Malaria Research Institute
Infection and Immunity | Year: 2014

Immunization with attenuated Plasmodium sporozoites or viral vectored vaccines can induce protective CD8+ T cells that can find and eliminate liver-stage malaria parasites. A key question is whether CD8+ T cells must recognize and eliminate each parasite in the liver or whether bystander killing can occur. To test this, we transferred antigen-specific effector CD8+ T cells to mice that were then coinfected with two Plasmodium berghei strains, only one of which could be recognized directly by the transferred T cells. We found that the noncognate parasites developed normally in these mice, demonstrating that bystander killing of parasites does not occur during the CD8+ T cell response to malaria parasites. Rather, elimination of infected parasites is likely mediated by direct recognition of infected hepatocytes by antigen-specific CD8+ T cells. © 2014, American Society for Microbiology.

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