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Biology
of Host-Parasite Relationships
These
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.
More: Host-Parasite Relationships
Immune
Responses and Immunity to Malaria
CDC
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 Malaria
Host 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 Resistance
CDC
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 Interaction
CDC 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.
See
also: Interaction of HIV and Malaria slide set
Methods
of Malaria Control
As
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 Evaluation
An
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 Insecticides
This 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:
- Evaluating and optimizing the use of new insecticides and/or their
formulations used for impregnating bed nets and personal protection;
- Implementing a program of research to increase the wash-durability
of insecticide-treated bed nets (ITNs) and evaluate the effectiveness
and wash-durability of existing commercial wash-durable ITNs;
- Providing analytical support in determining the quality of field
treatment of bed nets with insecticide used in field research and control
projects;
- Testing new and stored insecticide/pesticide formulation products
for conformity to published specifications to ensure their effective
and safe use;
- Assisting in the development and troubleshooting of appropriate specifications
for use in the purchase of insecticide/pesticide formulation products;
and
- Providing training in pesticide/insecticide analysis and formulation
testing.
WHO
Collaborating Center for the Identification and Typing of Insect Disease
Vectors
The 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
ELISAs
The 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 Vectors
The 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
Nets
Insecticide-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 gambiae
Since 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 gambiae
The 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 Sites
The 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
gambiae
The 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.
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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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