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To interrupt reproduction of the malaria parasite in the mosquito gut, Greg Garcia and Sheetij Dutta of Walter Reed Army Institute of Research seek to identify and block a gametocyte stage receptor for xanthreunic acid, which is known to trigger the differentiation of gametocytes, an essential step in the life-cycle of the malaria parasite.

Ron Raines of the University of Wisconsin proposes to convert a ribonuclease that rapidly degrades RNA into a zymogen, an enzyme precursor that is activated only when cleaved by an HIV protease. Because this cleaving can only occur within HIV-infected cells, the toxic activity of the ribonuclease will be unleashed only in cells in which HIV is active.

Ralph Albrecht of the University of Wisconsin in the U.S. seeks to develop magnetite nanoparticles conjugated to antibodies that will selectively bind to HIV-infected cells. Once bound to the infected cells, the magnetite is heated using an externally applied magnetic field; melting holes in the membrane of the infected cell and killing it.

Keith Jerome of the University of Washington in the U.S. will utilize a class of proteins called homing endonucleases, which have the ability to cut DNA sequences, to target the DNA sequences unique to HIV, thus disabling the virus from making any more copies of itself. This project’s Phase I research demonstrated that homing endonucleases can find a model virus hidden in the genes of infected cells. In Phase II, Jerome’s team is now modifying these proteins in hopes of producing several that can specifically target and destroy HIV within infected cells.

Xilin Zhao of the University of Medicine and Dentistry of New Jersey will test whether anaerobic gas, which causes rapid depletion of oxygen, will kill the tuberculosis bacteria without permanent damage to surrounding tissue.

Philip Bryan of the University of Maryland will use an engineered protease to destroy a specific Plasmodium surface protein that is essential in host cell invasion.

By using strips of mosquito netting around houses to turn the homes into mosquito traps, Jacques Derek Charlwood of Denmarks DBL Center for Health Research and Development, in conjunction with the INS of Mozambique, hopes to develop a simple new technique to reduce malaria transmission.

Jay Solnick of the University of California, Davis will explore whether the bacteria Helicobacter pylori, which can cause peptic ulcers in some people, might enhance immunity to tuberculosis and help maintain tuberculosis in a latent state.

Francis Nano of Canada’s University of Victoria will introduce essential genes found in Arctic bacteria into the genomes of “warm-loving” pathogens, making them unable to grow at core body temperatures. Such microbes could survive on human skin, which is cold enough to allow for replication and the stimulation of a strong immune system response, but not survive further dissemination into deeper and warmer tissue.

To test the hypothesis that immunization with a non-HIV antigen will neutralize the virus, Jinhua Xiang of the University of Iowa will determine if immunization with an envelope protein of the GB Virus C elicits antibodies that block HIV replication.

Dan Feldheim of the University of Colorado in the U.S. will test his hypothesis that gold nanocrystals coated with drug compounds can effectively inhibit protein-protein interactions that often drive disease pathogenesis, will be less susceptible to evolutionary mechanisms that lead to drug resistance, and offer enhanced drug delivery characteristics. This project’s Phase I research demonstrated that gold nanocrystals can be tailored to circumvent many viral and bacterial evolutionary drug resistance mechanisms. In Phase II, he is now studying the ability of small molecule-coated nanoparticles to withstand resistance mechanisms of Mycobacterium tuberculosis (TB).

Benjamin Chain of University College London will attempt to stimulate an antibody response against CCR5, a protein found in the body which is used by HIV to infect cells. By combining a small portion of the molecule with part of the tetanus bacterium, Chain hopes to overcome natural tolerance of CCR5 to deplete the presence of the protein and prevent a way for HIV to enter cells.

In an effort to enhance pathogen vulnerability to existing antibiotics, Angharad Davies of Swansea University in the U.K. proposes using peptides which activate stationary-phase microbes, leading to cell growth, with the aim of increasing susceptibility to established treatments.

Christina Smolke proposes to develop synthetic RNA devices that can process and transmit molecular input signals in hopes that this technology will result in more effective, targeted strategies for detecting and protecting against infectious disease.

To provoke an effective immune response against HIV, George Dickson of Royal Holloway –University of London will utilize HIV-based lentivectors encoded with a strong neutralizing epitope derived from tetanus toxin or influenza on its surface. By forcing production of such highly immunogenic and stable antigens, the immune system will respond with corresponding antibodies and control virus replication.

To test the theory neutralizing antibodies can be “programmed” to recognize broadly divergent HIV envelope proteins, Nancy Haigwood of Oregon Health & Science University will work to design components of an HIV vaccine using groups of related envelope sequences.

Allan Saul of the Novartis Vaccines Institute for Global Health in Italy will genetically modify gram-negative bacteria to generate large quantities of their outer membranes, which can be loaded with antigens that stimulate immune responses. This technology could prove to be a reliable and economic platform for generation of new vaccines.

Because cystic fibrosis patients and carriers appear to be resistant to tuberculosis, Jerry Nick of National Jewish Medical and Research Center in the U.S. will study whether mutations of the CFTR gene, which causes the disease, reduce or eliminate latent TB infection.

Ali Munawar of Molecmo Nanobiotechnologies in the U.S. aims to identify the specific protein that enables the HIV virus to access various sites within the host cell for replication. Identification of this protein will advance the development of a novel class of small molecule inhibitors that disrupt the HIV life cycle.

Humberto Lanz-Mendoza of Mexico’s Instituto Nacional de Salud Publica will test whether mosquitoes can become resistant to dengue and malaria by the introduction of non-virulent pathogens, which might stimulate immune priming and protect against subsequent infections. 

Carmenza Spadafora of Panama’s Institute of Advanced Scientific Investigations and High Technology Services and José A. Stoute of Pennsylvania State University College of Medicine in the U.S. investigated whether malaria can be treated by microwave irradiation, an idea based on the unique electromagnetic properties of hemozoin, a metabolite formed by Plasmodium parasites in infected red blood cells. This project’s Phase I research demonstrated that malaria parasites inside red blood cells are sensitive to low doses of microwaves that do not harm uninfected red blood cells. The Phase II grant (awarded to Dr. Stoute) will allow them to extend their results from the Phase I grant (awarded to Dr. Spadafora) by validating parasite killing effects in a mouse model of malaria and exploring the mechanism by which microwaves induce parasite death.

Employing new high throughput methods, antibiotic screening technologies and rapid genomic sequencing methods, George Church of Harvard University will partner with labs in South Africa to develop a new approach to identifying, studying, and limiting emerging drug resistance.

To generate the large numbers of infective malaria sporozites needed for use in an effective vaccine, James Kublin of the Fred Hutchinson Cancer Research Center in the U.S. will use high throughput screens to develop a library of media compounds needed to optimize in vitro production.

Anne Moscona of Weill-Cornell Medical College will investigate a new approach to treating respiratory viral disease by using artificial cell-like structures to present molecules that would attract the virus and activate the fusion mechanism it uses to enter cells. By triggering this mechanism prematurely, viruses can’t enter target cells and cause infection.

Brian Foy and Massamba Sylla of Colorado State University will research whether providing endectocides, drugs that kill parasitic worms, to animals and humans will effectively kill mosquitoes which feed on them. Through targeted and spaced drug administration, mosquitoes incubating disease-causing pathogens are expected to die prematurely, thus interrupting disease transmission, but these methods would limit the development of endectocide resistance.

Odile Ouwe Missi Oukem of Cameroon’s Centre International de Reference Chantal Biya will set up a suite of computer tools to manage and analyze biological, clinical and epidemiological data collected from African HIV-infected patients to better study HIV resistance to antiretroviral drugs.

Olen Kew of the Centers for Disease Control and Prevention in the U.S. will attempt to develop a safe and effective polio strain for use in an inactivated vaccine by modifying codon usage patterns in polio strains to control viral mutation rates, lower infectivity, and raise genetic stability.

Stephen Johnston of Arizona State University will investigate whether HIV causes deficient protein synthesis in infected cells. This knowledge could be used to stimulate normal human T cells to destroy infected cells based on these aberrant host antigens.

To optimize the effectiveness of current anti-tuberculosis drugs, Boitumelo Semete of the CSIR in South Africa will work with collaborators to develop “sticky nanoparticles” that specifically attach to TB-infected cells. Once taken in by these cells, the nanoparticles will slowly degrade, releasing the anti-TB drugs and killing the bacteria. With this novel drug delivery system, the team aims to improve the bioavailability of the current therapies, with the possibility of shortening the treatment period for TB as well as reduce drug side effects.

Because malnutrition, micronutrient deficiency and parasitic worm infection are all major risk factors for developing visceral leishmaniasis, Dinesh Mondal of International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) will study if VL development can be prevented in asymptomatic patients through nutritional supplements of vitamin A, zinc and iron, as well as anti-helminth treatment.

Guang-hong Tan of Hainan Provincial Key Laboratory of Tropical Medicine in China seeks to create a next-generation malaria vaccine by deleting a gene responsible for parasite development in the liver adding a new gene which attracts dendritic cells to the infection site. Using this modified sporozoite in a vaccine could produce a limited infection that, at the same time, induces a strong immune response against malaria.

Enterotoxigenic E. coli (ETEC) is the leading cause of diarrhea in the developing world. Roy Robins-Browne, of the University of Melbourne, in Australia will evaluate the effectiveness of a prototype vaccine that combines enterotoxin of E. coli (which lacks immunogenicity by itself) with another epitope to attract helper T cells and a lipid adjuvant to ensure delivery of the antigen directly into the cell.

Fasséli Coulibaly of Monash University in Australia will design a novel vaccine platform based on protein micro-crystals produced by insect viruses. Coulibaly will engineer vaccines that utilize this stable structure to present multiple antigens with a slow-release delivery, and will test their ability to induce a vigorous immune response without the need for refrigerated vaccine storage.

Gustavo Fioravanti Vieira of Universidade Federal do Rio Grande do Sul in Brazil will create 3-D computer models of viral epitopes anchored to major histocompatibility complex (MHC) molecules associated with different MHC alleles to search for “generalist” epitopes. Such epitopes can be used to develop viral vaccines that are effective against a broad spectrum of pathogens.  

Erich Cerny of Wissenschaftlicher Fonds Onkologie in Switzerland will test whether inducing antibodies against anti-malarial drugs can significantly prolong the half-life of that drug. Antibodies elicited via immunization may form a reservoir of the active drug for long-lasting treatment for malaria. Such a “small molecule vaccine” has significant implications for efficacy and cost of malaria prevention.