Bio:
I am working on the functional dissection the innate immune
system of malaria vector mosquito Anopheles which involves in defense
against Plasmodium parasites. Based on the knowledge we gain in the
lab model system I am seeking to develop novel strategies to control vector
transmitted diseases.
Current research:
Mosquitoes transmit a broad range of human parasitic and
viral diseases, within which
malaria is still today's most devastating infectious disease with a
worldwide prevalence of over 400 million cases and 2 million deaths per
year. Though
Anopheles mosquitoes are the major vectors of human malaria,
their ability to transmit malaria parasites are under large variations. The
dynamic immune interaction between the vector host and the malaria pathogen
determines the success of
Plasmodium development and continuation of the subsequent
disease transmission cycle. My goals are to determine the key components of
mosquito immune system in killing malaria parasites, and in a long run to
develop novel control strategies based on the transgenic approaches.
Previously and currently I was/am working on the following subjects:
1) Global transcriptomic comparison of Anopheles gambiae
immune responses to different pathogens. Successful
completion of the Plasmodium life cycle in the Anopheles vector is a key
component of malaria transmission. Major obstacles are encountered in the
midgut tissue, where most parasites are killed by the mosquito's immune
system. I was employing microarray based high throughput transcription
analyses and characterize mosquito response to parasites and bacteria. These
analyses permit selection of candidate key player genes of anti-Plasmodial
defense for further functional characterization. Using functional genomics
approaches I found the common genes which influence mosquito resistance to
both rodent and human malaria parasites. My study reveals that mosquitoes
mostly employ the same immune factors in defending against the two different
Plasmodium species. Also it suggests that mosquitoes have not evolved a
highly-specific defense against malaria parasites. Instead, they employ
factors of their antimicrobial defense system to combat the Plasmodium
parasite.
Work published: Dong et al., Anopheles gambiae Immune
responses to Human and Rodent Plasmodium Parasite Species, 2006. PLoS
Pathogens, 2: e52.
2) Identification of molecular mechanisms for mosquitoes to
achieve the pathogen recognition specificity. Insects do not have
antibodies, which are essential for pathogen recognition in humans. Instead,
insects rely on the innate immune system which is composed of cellular and
humoral defense mechanisms that are triggered by pattern recognition
receptor (PRR) molecules that are capable of specific binding to
pathogen-associated molecular patterns (PAMPs). I am interested in the
molecular mechanisms for achieving specificity of recognition in the insect
innate immune system, particular with the following gene and gene family:
a) AgDscam, a hypervariable immunoglobulin domain-containing
receptor of the A. gambiae innate immune system. Global transcriptomic
analysis has helped me to identify a molecule with the most interest,
AgDscam, the mosquito Down syndrome cell adhesion molecule, has strong
effect against malaria parasites and bacteria. The striking discovery is its
capability of generating over 31,000 potential alternative splice forms with
different combinations of adhesive domains and interaction specificities. It
has dual functions in the neuron and immune systems. Using molecular
biology, biochemistry, functional genomics and bioinformatics approaches, I
am studying the novel role of this gene in generating a broad range of PRRs
repertoires implicated in immune defense of mosquitoes, also investigating
the possible role of the transcriptional factors of the signal transduction
pathways in the regulation of its alternative splicing. My hypothesis is
that alternative splicing of AgDscam is in a way similar to antibodies;
different combinations of immunoglobulin domains, which are coded by spliced
exons, are used to produce a broad range of receptors. It suggests genetic
diversity is one of the most important mechanisms for insect immune systems
to achieve recognition diversity.
Work published:
Dong et al., AgDscam, a hypervariable
immunoglobulin domain-containing receptor of the Anopheles gambiae innate
immune system. 2006. 4: e229.
Updating of the project:
AgDscam poster. pdf
b) Fibrinogen-domain immuno-lectins, a large gene family
fighting against pathogens. Previous microarray assays also help us to
identify several FBN gene family members play important roles in the
mosquito innate immunity. The fibrinogen-domain immuno-lectin (FBN) family
is evolutionary conserved immune gene family between mammals and
invertebrates. The FBN proteins contain a pathogen-binding fibrinogen-like
domain at their C-terminus and the N-terminal sequence is implicated in the
formation of multimeric protein bundles with potential increased affinity
and specificity to the pathogens. The Drosophila genome harbours only 14 FBN
members while Anopheles gambiae has as many as 59 members. Using
bioinformatics approaches, molecular biology, biochemistry and cellular
biology approaches we are studying the functions of 39 members of this gene
family and reveal the reason for this remarkable expansion. FBN members have
complement and synergistic functions against pathogens which suggests
synergistic reaction as another major molecular mechanism for insect to
achieve recognition specificity.
Updating of the project:
FBN family poster .pdf
3) Functional genomics analysis of the implication of
mosquito midgut microbiota in the defense against malaria parasites.
Malaria transmitting mosquitoes are continuously exposed to
microbes, including their midgut microbiota. Previous studies have shown
that this naturally acquired microbial flora can modulate the mosquito's
vectorial capacity by inhibiting the development of Plasmodium and
other human pathogens through an unknown mechanism. I have undertaken a
comprehensive functional genomic approach to elucidate the molecular
interplay between the bacterial co-infection and the development of the
human malaria parasite Plasmodium falciparum in its natural vector
Anopheles gambiae. Global transcription profiling of septic
and aseptic mosquitoes identified a significant subset of immune genes that
were mostly up-regulated by the mosquito's microbial flora, including
several anti-Plasmodium factors. Aseptic mosquitoes without natural
bacterial flora displayed an increased susceptibility to Plasmodium
infection. Co-feeding of mosquitoes with bacteria and P. falciparum
gametocytes resulted in lower infection levels while thoracic injection with
live bacteria had no effect on the susceptibility to the parasite,
suggesting that tissue specific responses to bacteria are implicated in the
anti-Plasmodium defenses. Our data suggests the bacteria-mediated anti-Plasmodium
effect is mediated by the mosquitoes' antimicrobial immune responses,
plausibly through activation of basal immunity. We show that the microbiota
can modulate the anti-Plasmodium effects of some immune genes while
other kills the parasite independently of the bacteria. Overall, the
microbiota plays an essential role in modulating the mosquito's capacity to
sustain Plasmodium infection.
Updating of the project:
Mosquito microbiota .pdf
4) Currently I am also exploring transgenic approaches to
over-express effector molecules, recognition molecules and the
transcriptional factors aiming at developing malaria control strategies.
Updates will be available when transgenic mosquito generated.
Yuemei Dong PhD. current
CV
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