Biology Reference
In-Depth Information
ACh-induced contractions of H. contortus were found to be enhanced by
injecting KSAYMRFamide (AF8) whereas KHEYLRFamide (AF2) injec-
tions inhibited ACh-induced contraction. An additional observation
which involved testing AF8 on H. contortus isolates that were susceptible
or resistant to the cholinergic agonist levamisole revealed differential
sensitivity to the peptide, suggesting that its actions involve cholinergic
signaling.
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FLRFamide was reported to increase the body movements of
infective stage (J2) M. incognita.
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The application of reverse genetic approaches to parasitic nematodes
through the application of RNA interference (RNAi) has provided plat-
forms to interrogate the consequences of silencing the expression of
neuronal targets such as neuropeptides. Using RNAi, a small number of
flp genes have been silenced in infective stage G. pallida J2s (Gp-flp-1,
Gp-flp-6, Gp-flp-12, Gp-flp-14, and Gp-flp-18) and M. incognita J2s
(Mi-flp-18), in every case resulting in locomotory phenotypes including
various forms of reduced migrational competence or paralysis;
97,98
after
24 hours of RNAi-induced flp gene silencing, J2 stage migration through
sand columns was reduced between 71 and 100%. Recently, RNAi of the
Gp-flp-32 gene phenocopied RNAi of a putative Gp-flp-32 receptor gene in
infective stage worms, making themmigrate faster and appearing to have
no detrimental impact on plant infection.
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While it seems logical to
hypothesize that the silencing of a neuropeptide (or its cognate receptor)
that inhibits normal movement would result in “faster” worms, the
rationale for a parasite using a peptide in this way whenever there were
no observed detrimental effects of being faster is less obvious. This was
the first study to functionally deorphanize a parasite neuropeptide
receptor using reverse genetic approaches in whole worms.
FUTURE
PERSPECTIVES AND PARASITE C
ONTROL
The control of nematode parasites in humans and animals has relied
heavily on drugs that compromise normal neuromuscular function.
Most typically, these anthelmintics bind to ionotropic receptors that are
gated by classical neurotransmitters such as ACh, GABA or glutamate.
Overwhelming evidence demonstrates that the disruption of normal
neuromuscular function in nematode parasites is devastating for these
worms, compromising their viability as parasites and pathogens.
The large numbers of different nematode parasites that cause disease
mean that another expectation of drugs for the treatment of nematode
parasite infections is broad spectrum activity. Fortunately, many key
components of nematode neuromuscular function are well conserved
across diverse parasite species, providing opportunities for drugs which
disrupt this facet of nematode biology to have broad spectrum activities.
