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Cell
signaling and differentiation during host-parasite
interactions: the trypanosome model |
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pai 1. Model system:
the cellular differentiation from long
slender (LS) to short stumpy (SS)
forms We
propose to focus our studies on a model
system, which is the cellular
differentiation from long slender (LS) to
short stumpy (SS) forms. This
differentiation seems to depend on
activation of the cAMP signaling pathway.
The ULB group will analyze this signaling
cascade into some detail, in close
collaboration with the ITG partner and a
laboratory specialized in the field (M.
Boshart, MBB). 2. Studies on
surface receptors and
endocytosis The
work supported by the previous IAP
programme has led to new insights into
ligand uptake and proteins involved in
endocytosis in T. brucei in
particular, we have shown that N-linked
glycans containing linear stretches of
poly-N-acetyllactosamine (pNAL) are
specific to proteins from the endocytic
pathway. In collaboration with Dr.D. Nolan
(TCD), the ULB group will evaluate the
hypothesis that these glycans act as
sorting signals for endocytosis by
interacting with a specific trypanosomal
lectin. In addition, we propose to
characterize two additional transmembrane
proteins presumably linked to the
endocytotic machinery, a putative lectin
for high mannose and the surface receptor
pESAG1. Ongoing studies by the VUB on the
role of high mannose in the binding and
uptake of host macromolecules will be
pursued. Finally, a main effort will be
undertaken by all partners to elucidate
the mechanism by which a protein termed
SRA confers resistance to lysis by human
serum in T. rhodesiense, and a
putative receptor possibly involved in the
adaptation of T. gambiense to man
will be characterized. 3. Studies of
metabolic changes during
differentiation In
close collaboration with the ULB team and
with the help of ITG, the UCL group
proposes to study the turnover of
glycosomes and glycosomal enzymes during
the differentiation of T. brucei,
focusing on the LS-SS-Procyclic
transformation. Specific questions to be
addressed are: (1) Are new glycosomal
enzymes induced in a small subset of
existing glycosomes that can proliferate?
(2) Is the population of glycosomes
heterogeneous? (3) Are old,
non-proliferating glycosomes degraded by
autophagy? (4) Is the turnover of
glycosomes under the control of the same
signaling pathways as other
differentiation-associated changes
occurring on the surface and the endocytic
pathway ? 4.
Trypanosome-macrophage interactions During the previous
IAP program a detailed analysis was made
of the possible contribution of the
cytokine environment and macrophage
activation status in resistance to African
trypanosomosis. Collectively, these
results showed that trypanosomes can
elicit M1 and/or M2 types of macrophages
and that the M1/M2 balance may determine
the level of resistance to African
trypanosome infection. Future studies in
this area by the VUB and ULB groups will
focus on the following lines of
investigations: (1) In view of the
increasing evidence for distinctive roles
of M1 versus M2 cells in immunomodulation
and immunopathology, efforts will be
concentrated on a thorough genetical,
phenotypical and functional
characterization of trypanosome-elicited
M1/M2 cells. (2) The involvement of both
host and parasite components in the
induction and regulation of M1/M2 cells
will be further analyzed in depth, and
refined. 5.
Trypanosome-tsetse fly interactions Nothing
is known so far about the role of salivary
gland components in the development of the
parasite in the fly and the vertebrate
host. Based on progress achieved during
our previous IAP collaboration, the ITG
proposes to characterize a potential
candidate, and to develop new approaches
towards the identification of
immunomodulating components, with the help
of the ULB and VUB partners. |
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11 Mar 2003 |
objectives