Scientists advance plans to eliminate malaria

SCIENTISTS have made three major breakthroughs in the search for better treatment and control of malaria and the transmitting vector, female Anopheles mosquito.
      The latest of the three new findings is the modification of mosquitoes to produce sperm that will only create males, pioneering a fresh approach to eradicating malaria.
         Scientists from Imperial College London, in a study published in the journal Nature Communications, have tested a new genetic method that distorts the sex ratio of Anopheles gambiae mosquitoes, the main transmitters of the malaria parasite, so that the female mosquitoes that bite and pass the disease to humans are no longer produced.
     In the first laboratory tests, the method created a fully fertile mosquito strain that produced 95 per cent male offspring.
       The scientists introduced the genetically modified mosquitoes to five caged wild-type mosquito populations. In four of the five cages, this eliminated the entire population within six generations, because of the lack of females. The hope is that if this could be replicated in the wild, this would ultimately cause the malaria-carrying mosquito population to crash.
        This is the first time that scientists have been able to manipulate the sex ratios of mosquito populations. The researchers believe the work paves the way for a pioneering approach to controlling malaria.
        Also, a research team at the Institute for Biochemistry and Molecular Biology of the Faculty of Medicine and the Centre for Biological Signalling Studies BIOSS at the University of Freiburg, Germany, led by Prof. Dr. Carola Hunte has succeeded in describing how the antimalarial drug atovaquone binds to its target protein. The scientists used x-ray crystallography to determine the three-dimensional structure of the protein with the active substance bound.
         The drug combination atovaquone-proguanil (Malarone) is a medication used worldwide for the prevention and treatment of malaria. The data and the resulting findings concerning the mode of action of atovaquone could lead to improved medications against the tropical disease. Hunte and her team conducted the research at the Institute for Biochemistry and Molecular Biology of the Faculty of Medicine and the Centre for Biological Signalling Studies BIOSS at the University of Freiburg.
     The scientists published their findings in the journal Nature Communications.
      Also, researchers have found the first evidence of an intercellular bacterial infection in natural populations of two species of Anopheles mosquitoes, the major vectors of malaria in Africa. The infection, called Wolbachia, has been shown in labs to reduce the incidence of pathogen infections in mosquitoes and has the potential to be used in controlling malaria-transmitting mosquito populations.
          The study appears online June 6, 2014 in Nature Communications. Anopheles mosquitoes are the deadliest animal on the planet. They are responsible for transmitting malaria, which causes more than 600,000 deaths each year and puts half of the world’s population at risk for diseases.
        Wolbachia infections spread rapidly through wild insect populations by inducing a reproductive phenomenon called cytoplasm incompatibility (CI), and 66 per cent of arthropod species are infected. However, it was commonly thought that Anopheles mosquitoes were not natural hosts for Wolbachia infections, and attempts to identify infections in these mosquitoes in the field had failed.
          Malaria is one of the most dangerous tropical diseases in the world. Anopheles mosquitoes infected with Plasmodium species – unicellular parasites – transmit the disease by biting. Atovaquone blocks a protein of the respiratory chain in the mitochondria, the power plants of the cell, thus killing off the parasites. However, the pathogen is susceptible to mutations so that drug resistant strains are arising and spreading.
       Indeed, since 2000, increased prevention and control measures have reduced global malaria mortality rates by 42 per cent, but the disease remains a prevalent killer especially in vulnerable sub-Saharan African regions.
      Malaria control has also been threatened by the spread of insecticide resistant mosquitoes and malaria parasites resistant to drugs. According to latest estimates by the World Health Organization, over 3.4 billion people are at risk from contracting malaria and an estimated 627,000 people die each year from the disease.
        The Freiburg scientists have now paved the way for the development of improved drugs by revealing the precise binding mode of atovaquone to the target protein. They used the mitochondrial protein from cells of baker’s yeast for their analyses due to its close resemblance to the parasitic protein.
        The target protein of atovaquone is the third of four enzymes of the respiratory chain in the mitochondrion. The amino acid chains of the protein form a three-dimensional pocket. The molecule of the active substance fits perfectly into this pocket, binding to amino acids at numerous positions. These interactions are crucial for the effect atovaquone has in Plasmodium cells, ultimately leading to the death of the pathogen.
        The researchers conducted a protein sequence analysis, revealing that most of these docking sites are identical in the pathogen, baker’s yeast and in human cells. Atovaquone forms several bonds that are specific to the Plasmodium protein in the open area of the binding pocket. In addition, the structural analysis revealed the molecular basis of resistances: Due to mutations that change the structure of the target protein, the substance cannot reach the designated binding mode – it doesn’t fit perfectly into the pocket anymore.
      The data provides an important basis for improving antimalarial drugs. Scientists could now modify the molecular structure of atovaquone by means of structure-based drug design, ensuring that the active substance forms necessary bonds – and that the pathogen is no longer resistant to it.
          Associate professor of immunology and infectious diseases at Harvard School of Public Health (HSPH) and at the University of Perugia, Italy, said Flaminia Catteruccia, said: “Wolbachia is an interesting bacterium that seems perfectly suited for mosquito control. However, there were strong doubts that it could ever be used against field Anopheles populations.
       “We were thrilled when we identified infections in natural mosquito populations, as we knew this finding could generate novel opportunities for stopping the spread of malaria.”
       Co-author Francesco Baldini, from University of Perugia, Italy and HSPH, in collaboration with researchers from CNRS, France, collected Anopheles mosquitoes from villages in Burkina Faso, West Africa, and analyzed their reproductive tracts. Their objective was to identify all the bacteria in the reproductive systems of both male and female mosquitoes; they were not looking directly for Wolbachia. To their surprise, they found a novel strain of the infection, which they named wAnga.
        The researchers say they can now investigate whether the wAnga strain shares properties with other Wolbachia strains, which could make control strategies possible by inducing CI and reducing Plasmodium (the parasite that causes malaria) numbers in Anopheles mosquitoes in the field. “If successful, exploiting Wolbachia infections in malaria mosquitoes could reduce the burden of the disease globally,” said co-author Elena Levashina, from the Max Planck Institute for Infection Biology, Berlin.
      Lead researcher Professor Andrea Crisanti from the Department of Life Sciences at Imperial College London said: “Malaria is debilitating and often fatal and we need to find new ways of tackling it. We think our innovative approach is a huge step forward. For the very first time, we have been able to inhibit the production of female offspring in the laboratory and this provides a new means to eliminate the disease.”
        Dr Nikolai Windbichler, also a lead researcher from the Department of Life Sciences at Imperial College London, said: “What is most promising about our results is that they are self-sustaining. Once modified mosquitoes are introduced, males will start to produce mainly sons, and their sons will do the same, so essentially the mosquitoes carry out the work for us.”
       In this new experiment the scientists inserted a DNA cutting enzyme called I-PpoI into Anopheles gambiae mosquitoes. In normal reproduction, half of the sperm bear the X chromosome and will produce female offspring, and the other half bear the Y chromosome and produce male offspring.
         The enzyme that the researchers used works by cutting the DNA of the X chromosome during production of sperm, so that almost no functioning sperm carry the female X chromosome. As a result the offspring of the genetically modified mosquitoes was almost exclusively male.
It took the researchers six years to produce an effective variant of the enzyme.
      “The research is still in its early days, but I am really hopeful that this new approach could ultimately lead to a cheap and effective way to eliminate malaria from entire regions. Our goal is to enable people to live freely without the threat of this deadly disease,” concluded Dr Roberto Galizi from the Department of Life Sciences at Imperial College London.