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Biology of Host-Parasite RelationshipsThese studies aim to gain a better understanding of the relationships between malaria parasites, mosquito vectors, and vertebrate hosts, in order to improve or develop new methods to combat malaria. Such studies benefit from the facilities and resources available at CDC's malaria laboratories located in Chamblee, GA. These resources include colonies of different species of Anopheles mosquitoes collected from different geographic areas of the world where malaria is or can be transmitted. The mosquitoes are raised in a climate-controlled insectarium with additional rooms for secure biological containment of the malaria-infected vectors. The facilities also serve as a repository for the active collection and study of over a dozen species and numerous isolates of the malaria parasites that infect both human and non-human primates. The investigations are carried out in vivo in animals or mosquito vectors and in vitro where possible through tissue culture of the various parasite developmental stages. There is also a large modern AAALAC (American Association for the Accreditation of Laboratory Animal Care, International) approved animal facility at CDC (Chamblee) that provides access to a variety of non-human primate species that can serve as hosts for the different species of human and simian malaria parasites. This valuable resource provides transmission, infection and disease models for experiments that can be conducted only with these experimental animal models. Such experiments provide the knowledge that will facilitate the improvement and development of new malaria interventions through vaccines, chemotherapy, or transmission reduction and elimination.
Immune Responses and Immunity to MalariaCDC has unique biological samples available from malaria cohort studies designed to investigate the role of antibodies, cytokines and innate immune factors in protection against both uncomplicated malaria and severe malaria with anemia and cerebral involvement. These studies include birth cohort studies conducted in Kenya and ongoing cohort studies in India. Together these projects allow investigation of why manifestations of severe disease outcomes differ in various endemic settings (intense transmission versus seasonal transmission), how the transmission pressure affects development of immune responses, and what factors determine clinical and parasitological immunity. These questions are being addressed using various immunologic assays and molecular tools that include DNA microarrays and quantitative RT-PCR. Host Genetic Factors Associated with MalariaHost genetic factors influence dramatically the development and outcomes of severe disease states in malaria infections as well as the acquisition of immune status. Recent advances in human genome research have opened up new opportunities for identifying host genetic factors associated with severe disease outcomes and innate resistance factors that protect against morbidity and mortality due to malaria infections. Through our laboratory facilities and materials from our field-based cohort studies we are taking advantage of unique opportunities to identify potential host genetic factors associated with susceptibility to or protection from severe malarial anemia and cerebral malaria, or with protection from infection. Parasite Genetic Diversity and Drug ResistanceCDC is conducting ongoing investigations into how the genetic complexity of malaria infections affects disease, immunity, and transmission of factors such as drug resistance. The CDC malaria research programs are also characterizing the genetic diversity of important malaria vaccine candidate antigens, studies elemental to the development of vaccines effective against malaria. These studies also help to develop suitable molecular markers that could be used for tracking parasite populations associated with severe disease outcomes and to determine the conserved targets for vaccine development. CDC laboratories engaged in malaria research are developing molecular tools and networks to monitor emergence of drug-resistant malaria parasites globally. The laboratories collect, maintain in vivo and in vitro, and study parasite isolates with a wide array of defined drug-resistant phenotypes in order to identify and characterize the markers and mechanisms of drug resistance in malaria. These strains are available to qualified malaria researchers around the world. HIV and Malaria InteractionCDC studies were the first to recognize that during pregnancy HIV infection causes significant adverse impact on malaria. HIV infection increases the risk of malaria even among immune populations, increases the severity of infection, increases congenital transfer of malaria parasites to newborn babies, and reduces the effectiveness of anti-malarial prophylactic drugs. Current studies focus on how HIV infection influences the development and maintenance of antimalarial immune responses in pregnant women and children.
Methods of Malaria ControlAs part of the development program, new control strategies such as those involving candidate antimalarial vaccines and candidate antimalarial drugs are tested against currently circulating parasites to determine their potential for use in travelers and in endemic populations. Research using innovative treatment and control methods is conducted under rigid laboratory and field conditions. Vaccine Development and EvaluationAn effective vaccine against malaria would be a critical component to aid in the control of this disease. CDC scientists have an ongoing malaria vaccine development program. In addition, CDC scientists have been developing models of human malaria in small New World monkeys and using these nonhuman primate models to investigate the immunogenicity and protective efficacy of malaria vaccine candidates developed by scientific groups in the US and around the world. These primate malaria models are the only methods available to test the potential efficacy of human malaria vaccines prior to clinical trials. Scientists have been trying to develop an effective malaria vaccine for over 50 years and, thus, it is valid to ask if this quest is possible. Many scientists at CDC and around the world think that it is possible. People living in endemic areas who are repeatedly exposed to malaria, develop a functional immunity that controls the parasites in their blood, and that also protects them from severe disease. In addition, studies in animals and small-scale human clinical trials have shown that immunization with attenuated (weakened) parasites does stimulate an immunity that protects against a subsequent challenge of fully virulent and viable parasites. However, the challenges to develop a successful vaccine are great. There are 4 species of malaria that infect people, and each species is composed of a number of genetically different strains. Human genetic differences can also affect the level of immunity in response to a vaccine. In addition, during the course of malaria infection, the human host confronts four distinct life cycle stages: the invading sporozoite injected by the mosquito, separate replicating stages in the liver and the blood, and the mature sexual stages. Each of these life stages presents fresh antigens (targets) to the immune system. Therefore a vaccine against Plasmodium falciparum, the most serious malaria parasite, must account for the genetic diversity of both the parasite and the human host and provide effective immunity against different life cycle stages. To address the challenge, CDC scientists are developing multi-stage, multiple-target, artificial proteins for vaccine candidates (FALVAC) using selected antigenic epitopes (targets) from different life cycle stages. These epitopes have been shown to be involved in protection or are immunogenic and potentially protective under conditions of natural exposure. This epitope-based approach also provides the capability to account for the genetic diversity of the determinants. The recombinant protein molecules (FALVAC) are produced in bacteria following insertion of an artificially constructed gene. Immunization studies in animals of FALVAC-1 formulated with various adjuvants have demonstrated the induction of immune responses that recognize the different stages of the parasite, and show in vitro anti-parasitic activity. A second generation antigen (FALVAC-1A) is currently under evaluation. WHO Collaborating Center for Evaluating and Testing of New InsecticidesThis Collaborating Center carries out the following research and/or provides the following services to promote the effective and safe use of pesticides for disease-vector control:
WHO Collaborating Center for the Identification and Typing of Insect Disease VectorsThe purpose of this Collaborating Center is to provide training in traditional morphological-based identification of insect vectors of human diseases, in conjunction with development and distribution of reagents needed for, and training in, molecular-based methods. There is a need to train entomologists and vector control professionals in the use of dichotomous keys as such abilities have declined precipitously over the last few decades. As important disease vectors have been studied more intensely, species complexes have been identified and implicated in disease transmission. Members of many groups are indistinguishable morphologically, and other methods are needed for identification. WHO Collaborating Center for the Production and Distribution of Malaria Sporozoite ELISAsThe purpose of this Collaborating Center is to produce and distribute standardized malaria ELISA reagents for the identification of the mosquito vectors of malaria and to serve as a reference and training center for ELISA use. Since the inception of this program reagents have been distributed for use in studies in over 50 countries. WHO Collaborating Center for the Detection and Assessment of Insecticide Resistance in Insect Disease VectorsThe purpose of this Collaborating Center is to provide training in insecticide resistance detection, assessment and management for vector control professionals worldwide; to conduct research on basic principles of insecticide resistance, with an emphasis on evaluation and testing of insecticide-impregnated papers for pyrethroids and other insecticides; and to provide resistance analytical support and assistance to countries, particularly in Latin America, where insecticide resistance issues exist concerning the effective use of these compounds and insecticide treated materials for the control of arthropod disease vectors. Malaria Research and Reference Reagent Resource Center (MR4)CDC's Division of Parasitic Diseases (DPD) has a vital role in the Malaria Research and Reference Reagent Resource Center (MR4 ). As a subcontractor which provides vector - related materials, DPD keeps approximately 40 strains and species of Anopheles mosquitoes in continuous culture. These are provided to qualified MR4 users along with preserved material, genomic DNAs, information and primers. These allow continued research on standardized strains and provide reference material to private, government, and academic researchers. DPD has also donated numerous Plasmodium parasites into the MR4. Together, these constitute an unmatched biological resource. Development and Evaluation of Long-Lasting Insecticide-Treated NetsInsecticide-treated bed nets are advocated for the control and prevention of malaria in sub-Saharan Africa. However, widespread implementation of ITNs has been hampered by the need for frequent retreatment with insecticide. Several companies have developed long-lasting nets that theoretically retain effective concentrations of insecticide after long-term use and repeated washings. CDC has been active in developing new long-lasting treatment technologies as well as evaluating candidate long-lasting ITNs in the laboratory and the field. Larval Ecology of Anopheles gambiaeSince much of malaria vector control in the past has been focused on the adult mosquitoes, little is known about the biology of larval mosquitoes. Anopheles gambiae breeds in small, transient pools of water that are often formed due to human activity (e.g. hoofprints, drainage ditches, burrow pits, etc.). It has often been assumed that the diversity of habitats and their transient nature precludes interventions that target the immature stages. However, recent studies in western Kenya suggest that only a fraction of available habitats produce most of the adult mosquitoes. We are studying the factors that make habitats productive or not. This information will be used to design malaria vector control interventions that target larval mosquitoes. Characterizing Molecular Variation in Immune Response Genes of Anopheles gambiaeThe goal of this project is to evaluate the role of parasite-mediated selection in shaping molecular polymorphism in immune response genes of this important group of malaria vectors. The data collected will also be used to help understand the forces shaping susceptibility to malaria in natural mosquito populations and the implications of manipulating genes conferring mosquito refractoriness in nature. Evaluating Differences Between the Molecular Forms of Anopheles gambiae in Exploiting Different Breeding SitesThe goal of this project is to test the hypothesis that A. gambiae is being split into two species (so called M and S molecular forms) because each form is adapted to develop in different types of breeding site. Fieldwork conducted in Burkina Faso incorporates a novel transplantation experimental design. This information is required to quantify the productivity of various breeding sites to different malaria vectors. Identification of Adaptive Characters in Anopheles gambiaeThe goal of this project is to identify morphological, anatomical, and physiological characters that reflect adaptations of malaria vectors to local conditions (e.g., aridity) and to evaluate the contribution of genetic and environmental factors in shaping these variation patterns. This information is important for evaluating the prospects of mosquito control strategy based on large scale release of genetically manipulated insects or sterile males because if local adaptation is important, then the released individuals (which are assumed to be of different origin) are unlikely to affect the local population. Page last modified : April 23, 2004 Content source: Division of Parasitic Diseases National Center for Zoonotic, Vector-Borne, and Enteric Diseases (ZVED)
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