Bio:
I am a postdoctoral fellow in the
Dimopoulos lab since January, 2008, and have been working
on the dissection of the innate immune responses of
Aedes aegypti to dengue virus.
I'm now advancing to a new project that will involve the
generation and
characterization of hyper immune transgenic anopheline
mosquitoes resistant to
Plasmodium.
Current research:
Insects fight microbial infections by relatively simple but
efficient immune responses. The cellular immune responses are
mediated by hemocytes and can lead to phagocytosis,
encapsulation and clotting, whereas the humoral immune responses
are mediated by the so-called innate immune pathways that
ultimately promote the synthesis of antimicrobial peptides
(AMPs) and other effector molecules with anti-pathogen activity.
The
insect's innate immune responses are mainly orchestrated
by three different pathways: Toll, IMD and JAK-STAT. Toll and
IMD have widely been
characterized and linked to infections by gram-positive
bacteria, fungi and viruses (Toll) and gram-negative bacteria
(IMD).
On the other hand, less is known about the Janus kinase/Signal
Transducer and Activator of Transcription (JAK-STAT) pathway. In
the canonical JAK-STAT pathway, an extracellular ligand binds to
the transmembrane receptor Domeless (DOME) which suffers
conformational modification leading to the self-phosphorylation
of the associated Janus kinases (JAKs). The activated JAKs
phosphorylate DOME, resulting in the formation of docking sites
for the cytoplasmatic STATs. Recruitment of STATs by the
DOME/JAK complex leads to STATs phosphorylatation and
dimerisation, allowing translocation of STAT dimmers to the
nucleus and activation of specific target genes.
The
mechanisms by which insects counter viral infections without
having an acquired immunity is an intriguing, and at present,
relatively little is known about these anti-viral defense
systems.
D. melanogaster has been shown to use its RNAi
machinery and the Toll pathway to limit
Drosophila X
virus, and it uses its RNAi machinery and the JAK-Stat pathway
to limit Drosophila C virus. In A. aegypti, Sindbis virus
infection has been shown to induce the Toll pathway related Rel1
transcription factor and three transcripts of the
ubiquitin-ligase pathway genes, which are known regulators of
NFkB-like proteins. The RNAi machinery has also been linked to
the anti-dengue defense in
A. aegypti and
anti-O'nyong-nyong virus in
A. gambiae.
Similarly, limited knowledge on the anti-dengue
response in mosquitoes is available. With the completion of the
Aedes aegypti genome project in 2007 and the design of its
high-density DNA microarray, our lab has had a pioneering role
in dissecting the Aedes aegypti innate immune responses to
dengue virus. We have recently shown (Xi et al., 2008) that the
Toll pathway is activated by dengue and controls its infection.
Moreover, key JAK-STAT factors like DOME and SOCS were induced
by dengue, suggesting that this pathway is also activated upon
dengue infection.
In
my ongoing research project I'm interested in testing the
implication of the JAK-STAT pathway on the
mosquitoe's innate immune response to dengue virus.
Suppression of the JAK-STAT pathway by RNAi-mediated silencing
of the positive regulator DOME resulted in mosquitoes more
susceptible to dengue virus, whereas depletion of PIAS, a
negative regulator, led to less infection of dengue virus in the
midgut at 7 days post-blood meal, suggesting that the JAK-STAT
is part of the
mosquitoe's anti-dengue response. We are now dissecting
the JAK-STAT induced anti-dengue response, at the
transcriptional level, by using high-density DNA microarrays. We
have identified a few number of genes induced by JAK-STAT that
were also regulated by dengue virus in the
mosquitoe's carcass supporting the implication of the
JAK-STAT pathway in the anti-dengue defense (Fig. 3). I'm now
evaluating the role of these genes in modulating DENV-2
infection.
Jayme A. Souza-Neto Ph.D.
current C.V.
