MALARIA:
Malaria is transmitted by anopheline mosquitoes and
caused by protozoan parasites of the genus Plasmodium.
Plasmodium falciparum and
Plasmodium vivax are the most
serious. Symptoms of malaria are fever, chills, and
flu-like illness. Severe complications can develop if
left untreated. Approximately 515 million cases of
malaria occur worldwide each year, and over one million
people deaths, mostly young children in sub-Saharan
Africa. Bed nets, insecticides, and antimalarial drugs
are currently employed to fight malaria. Novel control
methods are urgently needed.
ARBOVIRUSES: Dengue
fever and dengue hemorrhagic fever are caused by dengue
viruses that belong to the Flavivirus genus. Four
antigenically distinct serotypes exist (DEN-1, DEN-2,
DEN-3, and DEN-4) and they are spread by Aedes mosquitoes.
Other important Aedes-transmitted viruses are Zika
Chikungunya and Yellow Fever virus. The
Aedes aegypti is the most common dengue vector while
Aedes albopictus is also emerging as a
potentially important vector. The geographic
distribution of arboviruses is similar to malaria but more
frequently associated to urban areas because of the
vectors capacity to adapt to these man-made
environments, threatening 2/3 of the human population.
INFECTION CYCLE:
The infection cycles of the malaria parasite and
arboviruses in their mosquito vectors are initiated by
the ingestion of blood from an infected host. Mosquitoes
feed on blood for egg production. The arboviruses will
infect the mosquito midgut epithelium (1), after
ingestion of infected blood, and replicate in the midgut
cells. Newly formed virus particles will escape from the
midgut cells into the hemolymph and eventually infect
and replicate in the salivary glands from where they
can infect a new host when mosquitoes feed on blood. The
gametocytes of the malaria parasite will fertilize in
the mosquito midgut lumen (3) and eventually form a
motile ookinete that will invade the midgut epithelium
(4) at 18-36 hours after ingestion of blood. The ookinete
will form an oocyst on the basal side of the midgut
epithelium that will mature over a period of
approximately 10 days. Thousands of sporozoites will
form in the oocyst and become released in the mosquito
hemolymph (5) and invade the salivary glands (2) from
where they can infect a new host when the mosquito feeds
on blood. The mosquito midgut represents the most
important barrier and bottleneck of infection and
transmission of pathogens, and is therefore a major area
of study.
MOSQUITO IMMUNE SYSTEM:
The mosquito vector immune system plays an important
role in regulating susceptibility to human pathogens
such as the malaria parasite and arboviruses. It
comprises immune signal transduction pathways of which
the TOLL, IMD and JAK-STAT are the best characterized.
The RNA interference (RNAi) pathway is a general
antiviral defense system. We are interested in how the
mosquito immune system fight human pathogens, and how it can be
genetically or transiently be manipulated to
confer resistance to infection, and block transmission
of disease. The IMD pathway is controlling
Plasmodium falciparum infection, while the TOLL,
JAK-STAT and RNAi pathways are implicated in controlling
arbovirus infection. We are also studying the implication of micro RNAs (miRNA) in regulating
anti-pathogen defenses in mosquito vectors. The
Dimopoulos Group has played a major role in studying
these immune pathways, effector systems and
immunity-related miRNAS. We are specifically interested
in immune factors that can
mediate recognition, immune response and pathogen
inhibition/killing.
MOSQUITO
MICROBIOTA:
The mosquito's intestinal microbiota (bacteria and
fungi) can influence susceptibility to pathogen
infection in multiple ways. Our studies focus on
microbes that exert pathogen inhibition through
anti-pathogen metabolites or by priming mosquito
immunity. Such microbes can be used for
the development of bio-control strategies for malaria
and dengue. Of special interest are bacteria that can
inhibit Plasmodium and dengue
virus in their respective mosquito vectors, exert insecticidal activity, and produce
secondary metabolites with in vitro
anti-pathogen and antibacterial activity.
The Dimopoulos Group has played a pioneering role in the
study of the mosquito vector microbiota.
HOST & RESTRICTION FACTORS:Pathogen host factors are
mosquito proteins that are required for pathogen
infection, and restriction factors are playing
pathogen antagonistic roles. Inhibition of host factors,
or overexpression of restriction factors, could thus
block infection and transmission of disease. We have identified and studied
several Plasmodium and arbovirus host/restriction factors,
and are further exploring their utility for the
development of novel vector-borne disease
control strategies.
MOSQUITO
TRANSGENESIS: The Dimopoulos Group
has played a pioneering role in the use of
transgenic technologies to genetically
manipulate mosquito vectors for resistance to
pathogen infection. We have genetically modified
the innate immune system of both Anopheles
and Aedes mosquitoes to render the
insects super-immune and resistant to human
pathogen infection. We have also created
mosquitoes that express foreign anti-pathogen
factors. We have used transposon-based random
integration, phiC31 docking site-directed
integration and CRISPR/CAS9 site-specific genome
editing technologies.
PARASITOLOGY CORE FACILITY:
The
Parasitology Core Facility supports
a variety of projects that focus on the
parasite’s interactions with the
mosquito vector and human host, and
other biological processes that are
relevant for its capacity to transmit
and infect. The facility comprises a
state-of-the-art tissue culture room
with relevant equipment. It provides
Plasmodium falciparum asexual blood-
and gametocyte-stage cultures, and both
human and rodent Plasmodium
sporozoite stages. Specialized services
are also provided upon request.
Department of Molecular Microbiology
& Immunoogy Johns Hopkins Malaria Research
Institute Bloomberg School of Public Health Johns Hopkins University
