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NEMATODES 335
obtain samples for analysis, almost nothing
is known about the composition of feces
from any nematode. Until the composition
and rate of production of this material is
determined for several species, it is impossible
to calculate the importance of defecation to
the overall process of waste elimination by
nematodes.
Considerations based on pharmacology
The importance of digestive tract function to
nematodes, though difficult to quantitate by
solute flux analyses, is readily deducible from
data showing that the gut is the principal target
for two of the three most widely used classes of
anthelmintics. The macrocyclic lactones, such
as ivermectin, target specific sets of motor neurons
that innervate the pharynx. Pharyngeal
pumping in C. elegans and various parasitic
species is inhibited by concentrations of ivermectin
that are 10–100-fold lower than those
required to reduce motility. Inhibition of the
ingestive process is probably sufficient for the
therapeutic actions of avermectins, since host
tissue levels of these drugs are much lower than
those required to affect worm movement
in vitro. The molecular target underlying pharyngeal
paralysis has been localized in C. elegans
to glutamate-gated Cl channels on two
motor neurons, M1 and M4, that innervate the
pharynx. These neurons, and their high level
of sensitivity to macrocyclic lactones, are conserved
in parasitic species. The importance of
gut function for survival is also demonstrated
pharmacologically by the benzimidazoles. The
earliest signs of worm toxicity are found in the
intestine, and include tubulin depolymerization
and inhibited transport of digestive secretory
vesicles in the anterior intestine. This is
followed by disintegration of the anterior intestine,
DNA fragmentation within anterior intestinal
nuclei, and inhibition of host erythrocyte
digestion.
Nematode intestinal proteins as targets for
vaccine development
Infectious stages of most nematodes rely on
intestinal functions for survival. Numerous
proteins have been characterized from the
microvillar surface of the nematode intestine.
Some of these proteins are not generally
exposed to the host (i.e. they are neither
co-localized on the cuticle nor secreted from
the worm) and elicited immune responses
when used to vaccinate host animals. These
gut proteins are often referred to as ‘hidden’ or
‘concealed’ antigens. Concealed antigens have
been most thoroughly studied in the bloodfeeding
gastrointestinal species, H. contortus.
Contortin, for example forms helical filaments
that extend into the glycocalyx that lines the
intestine, and contortin-enriched preparations
used to vaccinate lambs confer up to 78%
reduction in worm burdens following challenge
with infective larvae. Because contortin
is not usually exposed to the host, the response
it elicits is described as artificial immunity.
Other hidden antigens have been characterized.
A 110 kDa contaminant found in preparations
of contortin confers an even higher
level of protection (90%) when administered
to lambs in multiple immunizations. This glycoprotein,
called H11, has the predicted structure
of a type II integral membrane protein
with an N-terminal cytoplasmic tail, a transmembrane
domain and an extracellular region.
It has aminopeptidase A and M activities in
microsomal preparations, so probably functions
as a digestive enzyme in situ. It is localized
exclusively in the intestinal brush border, and
close homologs have been identified in other
gastrointestinal nematodes, including Teledorsagia
circumcincta and Ostertagia ostertagi.
Unfortunately, vaccine trials to determine the
cross-species protection conferred by H11 and
other hidden antigens have so far been disappointing.
Also, H11 and other hidden antigens
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