trans

NEMATODES 327
The transcuticular excretion of organic acids
has important implications for how charged
molecules, including weakly acidic or basic
drugs, are absorbed across the cuticle. Organic
acid excretion drives the pH within the aqueous
pores to values close to the aggregate pK a of the
excreted acids. The pH of weakly buffered
medium containing adult A. suum, for example,
which excretes predominantly branched
chain fatty acids with pK a s in the range of
4.76–4.88, approaches pH 5.0 during extended
incubations. Species that excrete higher levels
of lactic acid, such as B. pahangi, tend to acidify
the medium even more because of the lower
pK a of lactic acid. This effect is most pronounced
in the protected microenvironment of
aqueous-filled pores that traverse the cuticle, as
shown experimentally for A. suum and H. contortus.
Rates of uptake of several model permeants,
including weak acids and weak bases, do
not vary as a function of pH in the medium. The
rates of absorption and pattern of tissue distribution
of model weak acids and bases are unaltered
by mechanical or chemical ligation, or by
marked changes in the pH or buffer capacity of
the bulk medium, even though ligation blocks
the uptake of large, hydrophilic molecules, such
as inulin or dextrose, by 98%. These findings
demonstrate that a large fraction of solutes is
absorbed across the cuticle, and that absorption
of weak acids and bases is dependent on
pH within the aqueous pores, not that of the
bulk medium (or, presumably, the pH of host
body fluids).
Immune evasion
Adult stages of some parasitic nematodes can
persist in immunocompetent hosts for many
years. During the course of an infection, leukocytes,
antibodies, complement and various oxidants
are targeted to the worm surface, but
generally have little effect on worm viability.
This aspect of the nematode–host relationship
is reason enough to conclude that parasites
have evolved effective mechanisms for evading
all components of the host’s immune system.
Consideration of the gross structural properties
of the cuticle alone is instructive in this regard.
The nematode cuticle, with its tough and relatively
inert physical structure, has long been
presumed to be a protective shell that excludes
host immune effectors, most of which are far
too large to penetrate the small aqueous pores
that traverse it.
Cuticular glycolipids also contribute to
immune evasion by protecting surface proteins
from degradation by host proteases. In vitro
studies on filarial nematodes show that surface
proteins are degraded by host proteases
only after the worm’s surface is treated with
agents that disrupt the glycolipid barrier.
Other parasites, including Leishmania spp.,
employ glycolipids to mask their surface from
host immune effectors, and it is possible
that cuticular glycolipids serve a similar role.
However, the surface of the nematode cuticle,
by itself, is not highly immunogenic. For most
species, the cuticle contains only a limited set
of exposed proteins, glycoproteins and glycolipids.
When purified and injected into animals,
these molecules generally elicit weak
immune responses and fail to significantly
protect against infection. Indeed, molecules
that adhere to or are released by the cuticle
may suppress attack by the immune system or
diminish damage caused by noxious agents
released by leukocytes onto the parasite surface.
For example, a selenium-independent
glutathione peroxidase is expressed in the
cuticle of late fourth stage larvae and adult
D. immitis. This antioxidant counters the effects
of oxidants released by host leukocytes. In
addition to its putative role as an antioxidant,
surface-associated glutathione peroxidase may
also contribute directly to new cuticle synthesis
and repair, as it may catalyze formation
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS