Activation of Nippostrongylus brasiliensis infective larvae is regulated by a pathway distinct from the hookworm Ancylostoma caninum

Huang, Simo; Chan, Denice T. Y.; Smyth, Danielle J.; Ball, G.; Gounaris, Kleoniki; Selkirk, Murray E.

doi:10.1016/j.ijpara.2010.06.004

Cited by 28 publications

(48 citation statements)

References 43 publications

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“…Using a previously established S. stercoralis L3i feeding assay [16], [68], we demonstrated that exogenous application of the membrane-permeable cGMP analog 8-bromo-cGMP stimulates L3i activation (Figure 2A) with a higher potency than that observed in experiments with other parasitic nematodes [51]–[53]. Furthermore, 8-bromo-cGMP activated L3i more quickly than a mixture of host-like biochemical cues (Figure 2B).…”

Section: Discussionmentioning

confidence: 72%

“…A similar pathway—and accompanying increase in cGMP—has been described in C. elegans in response to odorants [81]. Additionally, other research groups have used the membrane-permeable analog of cGMP, 8-bromo-cGMP, to test whether increases in cGMP can activate L3i in place of host-like cues in Ancylostoma caninum [52], Ancylostoma ceylanicum [51], and Nippostrongylus brasiliensis [53]. In these three hookworm species (clade 9B) [54], which are closely related to C. elegans (clade 9A), 8-bromo-cGMP activates L3i at 5 mM for A. caninum and A. ceylanicum and at 500 µM for N. brasiliensis .…”

Section: Resultsmentioning

confidence: 89%

“…We hypothesized that the cGMP-regulated chemosensory pathway may be one of the first to transduce host cues when S. stercoralis L3i encounter a permissive host. This hypothesis was based on our previous observation that the transcripts of multiple cGMP pathway components are increased in S. stercoralis L3i, suggesting that this pathway may be “poised” to transduce host cues [14], and studies demonstrating that exogenous application of 8-bromo-cGMP activates L3i of hookworm species [51]–[53]. We therefore sought to describe the components of a chemosensory 7TM GPCR signaling pathway in S. stercoralis and determine whether cGMP signaling regulates L3i activation as well as IIS and other signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

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cGMP and NHR Signaling Co-regulate Expression of Insulin-Like Peptides and Developmental Activation of Infective Larvae in Strongyloides stercoralis

2014

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The infectious form of the parasitic nematode Strongyloides stercoralis is a developmentally arrested third-stage larva (L3i), which is morphologically similar to the developmentally arrested dauer larva in the free-living nematode Caenorhabditis elegans. We hypothesize that the molecular pathways regulating C. elegans dauer development also control L3i arrest and activation in S. stercoralis. This study aimed to determine the factors that regulate L3i activation, with a focus on G protein-coupled receptor-mediated regulation of cyclic guanosine monophosphate (cGMP) pathway signaling, including its modulation of the insulin/IGF-1-like signaling (IIS) pathway. We found that application of the membrane-permeable cGMP analog 8-bromo-cGMP potently activated development of S. stercoralis L3i, as measured by resumption of feeding, with 85.1±2.2% of L3i feeding in 200 µM 8-bromo-cGMP in comparison to 0.6±0.3% in the buffer diluent. Utilizing RNAseq, we examined L3i stimulated with DMEM, 8-bromo-cGMP, or the DAF-12 nuclear hormone receptor (NHR) ligand Δ7-dafachronic acid (DA)—a signaling pathway downstream of IIS in C. elegans. L3i stimulated with 8-bromo-cGMP up-regulated transcripts of the putative agonistic insulin-like peptide (ILP) -encoding genes Ss-ilp-1 (20-fold) and Ss-ilp-6 (11-fold) in comparison to controls without stimulation. Surprisingly, we found that Δ7-DA similarly modulated transcript levels of ILP-encoding genes. Using the phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitor LY294002, we demonstrated that 400 nM Δ7-DA-mediated activation (93.3±1.1% L3i feeding) can be blocked using this IIS inhibitor at 100 µM (7.6±1.6% L3i feeding). To determine the tissues where promoters of ILP-encoding genes are active, we expressed promoter::egfp reporter constructs in transgenic S. stercoralis post-free-living larvae. Ss-ilp-1 and Ss-ilp-6 promoters are active in the hypodermis and neurons and the Ss-ilp-7 promoter is active in the intestine and a pair of head neurons. Together, these data provide evidence that cGMP and DAF-12 NHR signaling converge on IIS to regulate S. stercoralis L3i activation.

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Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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cGMP and NHR Signaling Co-regulate Expression of Insulin-Like Peptides and Developmental Activation of Infective Larvae in Strongyloides stercoralis

2014

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“…In parasitic nematodes, the resumption of feeding has been used as a phenotypic marker in an in vitro activation assay (Hawdon et al, 1993; Brand and Hawdon, 2004; Cantacessi et al, 2010; Huang et al, 2010; Stoltzfus et al, 2012a), and the PI3 kinase inhibitor LY294002 effectively blocks resumption of feeding (Brand and Hawdon, 2004; Stoltzfus et al, 2012a). This phenomenon suggests that the IIS pathway might be conserved and regulates the activation of iL3 in strongylid nematodes.…”

Section: Discussionmentioning

confidence: 99%

Hc-daf-2 encodes an insulin-like receptor kinase in the barber’s pole worm, Haemonchus contortus, and restores partial dauer regulation

Lok

Gasser

et al. 2014

International Journal for Parasitology

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Infective L3s (iL3s) of parasitic nematodes share common behavioural, morphological and developmental characteristics with the developmentally arrested (dauer) larvae of the free-living nematode Caenorhabditis elegans. It is proposed that similar molecular mechanisms regulate entry into or exit from the dauer stage in C. elegans, and the transition from free-living to parasitic forms of parasitic nematodes. In C elegans, one of the key factors regulating the dauer transition is the insulin-like receptor (designated Ce-DAF-2) encoded by the gene Ce-daf-2. However, nothing is known about DAF-2 homologues in most parasitic nematodes. Here, using a PCR-based approach, we identified and characterised a gene (Hc-daf-2) and its inferred product (Hc-DAF-2) in Haemonchus contortus (a socioeconomically important parasitic nematode of ruminants). The sequence of Hc-DAF-2 displays significant sequence homology to insulin receptors (IR) in both vertebrates and invertebrates, and contains conserved structural domains. A sequence encoding an important proteolytic motif (RKRR) identified in the predicted peptide sequence of Hc-DAF-2 is consistent with that of the human IR, suggesting that it is involved in the formation of the IR complex. The Hc-daf-2 gene was transcribed in all life stages of H. contortus, with a significant up-regulation in the iL3 compared with other stages. To compare patterns of expression between Hc-daf-2 and Ce-daf-2, reporter constructs fusing the Ce-daf-2 or Hc-daf-2 promoter to sequence encoding GFP were microinjected into the N2 strain of C. elegans, and transgenic lines were established and examined. Both genes showed similar patterns of expression in amphidial (head) neurons, which relate to sensation and signal transduction. Further study by heterologous genetic complementation in a daf-2-deficient strain of C. elegans (CB1370) showed partial rescue of function by Hc-daf-2. Taken together, these findings provide a first insight into the roles of Hc-daf-2/Hc-DAF-2 in the biology and development of H. contortus, particularly in the transition to parasitism.

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“…In H. contortus, 5-HT was detected in amphid and pharyngeal neurons, and in male-specific neurons, whereas dopamine was only found in motor neuron commissures; application of either caused inhibition of movement, in the case of dopamine this was confined to the central part of the worm (Rao et al, 1987). Exogenous 5-HT also stimulates feeding in A. suum and Nippostrongylus brasiliensis (Brownlee et al, 1997;Trim et al, 2001;Huang et al, 2010). By contrast, it had no effect on the contractile activity of Dirofilaria immitis (Bowen and Vitayavirasak, 2008).…”

Section: G Protein-coupled Receptorsmentioning

confidence: 90%

Ion channels and receptor as targets for the control of parasitic nematodes

Wolstenholme

2011

International Journal for Parasitology: Drugs and Drug Resistan

100

103

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Many of the anthelmintic drugs in use today act on the nematode nervous system. Ion channel targets have some obvious advantages. They tend to act quickly, which means that they will clear many infections rapidly. They produce very obvious effects on the worms, typically paralyzing them, and these effects are suitable for use in rapid and high-throughput assays. Many of the ion channels and enzymes targeted can also be incorporated into such assays. The macrocyclic lactones bind to an allosteric site on glutamate-gated chloride channels, either directly activating the channel or enhancing the effect of the normal agonist, glutamate. Many old and new anthelmintics, including tribendimidine and the amino-acetonitrile derivatives, act as agonists at nicotinic acetylcholine receptors; derquantel is an antagonist at these receptors. Nematodes express many different types of nicotinic receptor and this diversity means that they are likely to remain important targets for the foreseeable future. Emodepside may have multiple effects, affecting both a potassium channel and a pre-synaptic G protein-coupled receptor; although few other current drugs act at such targets, this example indicates that they may be more important in the future. The nematode nervous system contains many other ion channels and receptors that have not so far been exploited in worm control but which should be explored in the development of effective new compounds.

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Activation of Nippostrongylus brasiliensis infective larvae is regulated by a pathway distinct from the hookworm Ancylostoma caninum

Cited by 28 publications

References 43 publications

cGMP and NHR Signaling Co-regulate Expression of Insulin-Like Peptides and Developmental Activation of Infective Larvae in Strongyloides stercoralis

cGMP and NHR Signaling Co-regulate Expression of Insulin-Like Peptides and Developmental Activation of Infective Larvae in Strongyloides stercoralis

Hc-daf-2 encodes an insulin-like receptor kinase in the barber’s pole worm, Haemonchus contortus, and restores partial dauer regulation

Ion channels and receptor as targets for the control of parasitic nematodes

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