Biology Reference
In-Depth Information
Considering their relative conservation and crucial functions in
membrane and vesicle transport, signal transduction, cell division, and
differentiation as well as the regulation of transcription and translation,
GTPases are another key group of enzymes suitable as targets for anti-
parasitic drugs.
74
Based on homology with molecules in
C. elegans
,
169 GTPases are encoded in the
A. suum
genome, including 135 small
GTPases (Ras superfamily) representing the Rab, Ras, Rho, and Ran
subfamilies. Examples of these homologues include
eft-1
,
fzo-1
,
glo-1
, and
rho-1
, which play essential roles in embryonic, larval, and/or reproduc-
tive development (see
www.wormbase.org
)
. Given the important roles
that GTPases play in a range of species,
76
such molecules are likely to be
essential in
A. suum
and other parasitic nematodes and, thus, also
represent an attractive class of enzymes worthy of in-depth functional
exploration toward drug discovery.
Key Molecules Involved in Parasite
e
Host
Interactions
ES Peptides
ES peptides are central to understanding the immunological rela-
tionship between a parasite and its host. We predicted the secretome of
A. suum
to comprise at least 775 proteins with diverse functions. Notable
among them are
e
70 secreted proteases (including families S9, S3, M12,
and C1) which have known roles in host-tissue degradation, required for
feeding, tissue penetration, and/or larval migration for a range of
helminths,
60
including
Ascaris
1
and in inducing and modulating
host immune defences.
61,77
Indeed nearly half of the proteins repre-
senting the predicted
A. suum
secretome are homologues of peptides
with immunomodulatory or immunogenic activity in other parasites
61
(see
Tabl e 11 .3
). Most abundant among them are O-linked glycosylated
proteins (
n
w
300), which are targeted by various pattern recognition
receptors associated with host dendritic cells and by IgM antibodies, and
linked to a Th2 immune response.
61
Other members of the
A. suum
secretome are predicted to direct or evade immune responses, including
an ES-62 leucyl aminopeptidase homologue, which has been shown to
inhibit B-cell, T-cell, and mast cell proliferation/response, promote an
alternative activation of the host macrophages, through the inhibition of
the Toll-like receptor signaling pathway, and induce a Th2 response
through the inhibition of IL-12p70 production by dendritic cells.
61
Additional, immunomodulatory molecules predicted from the
A. suum
secretome include homologues of the
B. malayi
cystatin CPI-2 (i.e.
another B-cell inhibitor), several TGF-
ΒΌ
b
and macrophage initiation factor
mimics, neutrophil inhibitors, various oxidoreductases, and close
homologues of platelet anti-inflammatory factor
.
61
The
A. suum
ES
peptides which appear to have a role in immune evasion include
homologues of various galectins,
a
thought
to mimic host proteins
