Hookworm larval infectivity, arrest and amphiparatenesis: the Caenorhabditis elegans daf-c paradigm

Hotez, Peter J.; Hawdon, John M.; Schad, Gerhard A.

doi:10.1016/0169-4758(93)90159-d

Cited by 128 publications

(109 citation statements)

References 35 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…The "dauer hypothesis" proposes that similar molecular signalling pathways control the entry into and exit from arrested development in C. elegans and in parasitic nematodes [65,66]. Heterologous complementation showed that the main components of insulin-like signalling, including daf-16, daf-2, age-1 and daf-12 in parasitic nematodes [37,[39][40][41]67], have similar functions to C. elegans orthologues.…”

Section: Discussionmentioning

confidence: 99%

Exploring the role of two interacting phosphoinositide 3-kinases of Haemonchus contortus

Gasser

Lok

et al. 2014

Parasites & Vectors

View full text Add to dashboard Cite

Background: Phosphoinositide 3-kinases (PI3Ks) are relatively conserved and important intracellular lipid kinases involved in signalling and other biological pathways. In the free-living nematode Caenorhabditis elegans, the heterodimeric form of PI3K consists of catalytic (AGE-1) and regulatory (AAP-1) subunits. These subunits are key components of the insulin-like signalling pathway and play roles in the regulation of the entry into and exit from dauer. Although, in parasitic nematodes, similar components are proposed to regulate the transition from free-living or arrested stages to parasitic larvae, nothing is known about PI3Ks in relation to the transition of third-stage larvae (L3s) to parasitism in Haemonchus contortus.

show abstract

Section: Discussionmentioning

confidence: 99%

Exploring the role of two interacting phosphoinositide 3-kinases of Haemonchus contortus

Gasser

Lok

et al. 2014

Parasites & Vectors

View full text Add to dashboard Cite

show abstract

“…Interestingly, iL3 larvae resemble the dauer larvae of the free-living nematode Caenorhabditis elegans in that they are all nonfeeding, developmentally arrested, dormant filariform larvae with a sealed buccal capsule and thickened body wall cuticle, enabling them to survive environmental challenges (8). Like C. elegans dauer larvae, iL3 recover from their arrested development once they enter a proper environment (i.e., their respective hosts) (9).…”

mentioning

confidence: 99%

Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes

Wang

Zhou

Motola

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

114

238

View full text Add to dashboard Cite

Nematode parasitism is a worldwide health problem resulting in malnutrition and morbidity in over 1 billion people. The molecular mechanisms governing infection are poorly understood. Here, we report that an evolutionarily conserved nuclear hormone receptor signaling pathway governs development of the stage 3 infective larvae (iL3) in several nematode parasites, including Strongyloides stercoralis, Ancylostoma spp., and Necator americanus. As in the free-living Caenorhabditis elegans, steroid hormone-like dafachronic acids induced recovery of the dauer-like iL3 in parasitic nematodes by activating orthologs of the nuclear receptor DAF-12. Moreover, administration of dafachronic acid markedly reduced the pathogenic iL3 population in S. stercoralis, indicating the potential use of DAF-12 ligands to treat disseminated strongyloidiasis. To understand the pharmacology of targeting DAF-12, we solved the 3-dimensional structure of the S. stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes.dafachronic acid ͉ parasitology ͉ pharmacology ͉ X-ray crystal structure P arasitic nematodes constitute a large family of pathogens that infect hosts ranging from plants and animals to people, causing great economic loss and worldwide health threats (1, 2). One of the most problematic parasites, Strongyloides stercoralis, is estimated to infect 100-200 million people. Primary infections are often asymptomatic and clinically silent in immunocompetent individuals. However, once the immune system is compromised (e.g., by corticosteroid therapy), the parasite establishes autoinfection cycles that result in a frequently fatal disseminated strongyloidiasis (3, 4). Hookworms (Ancylostoma and Necator spp.) are other parasitic nematodes that affect Ͼ1 billion people and are the dominant cause for iron-deficient anemia worldwide (2). Oral administration of anthelmintics such as benzimidazoles (microtuble toxins) and ivermectin (a neurotoxin) is currently the preferred treatment for nematode infections (5). However, no reliable options exist for treating the more severe form of disseminated strongyloidiasis (6). Moreover, resistance to the anthelmintics has become widespread in animals and is beginning to occur in humans (2, 7). Therefore, studying the mechanisms that govern nematode life cycles is an attractive approach to identifying new therapeutic targets.Infection of hosts by parasitic nematodes is mediated by infective larvae, which in S. stercoralis and hookworm are the third stage or L3 larvae (iL3) (4, 5). Interestingly, iL3 larvae resemble the dauer larvae of the free-living nematode Caenorhabditis elegans in that they are all nonfeeding, developmentally arrested, dormant filariform larvae with a sealed buccal capsule and thickened body wall cuticle, enabling them to survive environmental challenges (8). Like C. elegans dauer larvae, iL3 recover from their ar...

show abstract

“…1A). IJs are developmentally arrested, third-stage larvae analogous to the dauer stage of freeliving nematodes (7). IJs actively seek out insect hosts using chemosensory cues (8)(9)(10) and infect either by entering through natural body openings or by penetrating the insect cuticle (11).…”

mentioning

confidence: 99%

Variation in the Susceptibility of Drosophila to Different Entomopathogenic Nematodes

2015

View full text Add to dashboard Cite

Entomopathogenic nematodes (EPNs) in the genera Heterorhabditis and Steinernema are lethal parasites of insects that are of interest as models for understanding parasite-host interactions and as biocontrol agents for insect pests. EPNs harbor a bacterial endosymbiont in their gut that assists in insect killing. EPNs are capable of infecting and killing a wide range of insects, yet how the nematodes and their bacterial endosymbionts interact with the insect immune system is poorly understood. Here, we develop a versatile model system for understanding the insect immune response to parasitic nematode infection that consists of seven species of EPNs as model parasites and five species of Drosophila fruit flies as model hosts. We show that the EPN Steinernema carpocapsae, which is widely used for insect control, is capable of infecting and killing D. melanogaster larvae. S. carpocapsae is associated with the bacterium Xenorhabdus nematophila, and we show that X. nematophila induces expression of a subset of antimicrobial peptide genes and suppresses the melanization response to the nematode. We further show that EPNs vary in their virulence toward D. melanogaster and that Drosophila species vary in their susceptibilities to EPN infection. Differences in virulence among different EPN-host combinations result from differences in both rates of infection and rates of postinfection survival. Our results establish a powerful model system for understanding mechanisms of host-parasite interactions and the insect immune response to parasitic nematode infection. E ntomopathogenic nematodes (EPNs) of the genera Steinernema and Heterorhabditis are insect-parasitic nematodes that are phylogenetically distant but share a similar life cycle as a result of convergent evolution (1). EPNs offer numerous advantages as model parasitic nematodes, including small size, short generation time, and amenability to in vitro culturing (2). EPN infective larvae are associated with bacterial endosymbionts: Steinernema species are associated with bacteria in the genus Xenorhabdus, and Heterorhabditis species are associated with bacteria in the genus Photorhabdus (1). At least some EPNs are capable of infecting the fruit fly Drosophila melanogaster, providing a genetically tractable system for understanding the immune response to parasitic nematodes and their bacterial endosymbionts (3-6). However, the insect immune response to EPN infection is poorly understood.During a particular developmental stage called the infective juvenile (IJ), EPNs infect insects (Fig. 1A). IJs are developmentally arrested, third-stage larvae analogous to the dauer stage of freeliving nematodes (7). IJs actively seek out insect hosts using chemosensory cues (8-10) and infect either by entering through natural body openings or by penetrating the insect cuticle (11). IJs harbor their bacterial endosymbiont in their gut and deposit it into the insect upon infection, where it assists the nematode in killing the insect, digesting insect tissues, and inhibiting the growth of o...

show abstract

Hookworm larval infectivity, arrest and amphiparatenesis: the Caenorhabditis elegans daf-c paradigm

Cited by 128 publications

References 35 publications

Exploring the role of two interacting phosphoinositide 3-kinases of Haemonchus contortus

Exploring the role of two interacting phosphoinositide 3-kinases of Haemonchus contortus

Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes

Variation in the Susceptibility of Drosophila to Different Entomopathogenic Nematodes

Contact Info

Product

Resources

About