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PubMed2004

Infective larvae of the human hookworms Necator americanus and Ancylostoma duodenale differ in their orientation behaviour when crawling on surfaces.

The infective third stage larvae of hookworms infect their hosts by active skin invasion, and they find and recognize their hosts by the behavioural phases of activation, directed crawling, and penetration. Here we analyse the orientation of the infective larvae of the human hookworms Necator americanus and Ancylostoma duodenale when crawling on surfaces. Their behaviour differed from that of the larvae of the dog hookworm Ancylostoma caninum, but the two species also differed from each other. N. americanus crawled towards light, but A. duodenale did not. Both species migrated towards the warm ends of thermal gradients, and this response was more sensitive than in other skin-invading helminths (threshold 0.09 degrees C/cm). However, A. duodenale turned back and accumulated at higher temperatures than N. americanus [turn-back 45.7 (44.5-49.9) vs 41.5 (38.5-43.9) degrees C; accumulation 43.6 (41.6-46.0) vs 39.5 (37.9-43.0) degrees C]. In contrast to other skin-invading helminths, both species showed no chemo-orientation towards skin compounds when crawling on surfaces. This behaviour may reflect adaptations for reaching the skin surface from hairs or adhering material, but the differences in the orientation of the two species could not be attributed to differing transmission strategies.

Ancylostoma↗

PubMed2004

Behavioural strategies used by the hookworms Necator americanus and Ancylostoma duodenale to find, recognize and invade the human host.

The infective third-stage larvae of the hookworms Necator americanus and Ancylostoma duodenale infect their human hosts by active skin invasion, but A. duodenale is in addition capable of oral infection. The behaviour of the larvae when crawling on surfaces has already been described. Here we analyse in various in vitro systems the other behavioural invasion phases: activation, penetration, and orientation within the host. The larvae normally remained in a motionless, energy-saving, resting posture. An activation to sinusoidal locomotion was stimulated in both species by similar cues such as touch, vibration, water currents, heat, light, and chemicals. Human breath in addition stimulated searching and waving ("nictating") behaviour, which facilitates a change-over to the host. Activating cues in air streams were warmth and moisture; CO2 activated only in combination with warmth and/or moisture. Penetration behaviour in both species was stimulated by warmth and skin extracts. The stimulating components of skin extracts were fatty acids, but their stimulating characteristics differed from those inducing schistosome cercarial skin penetration. After penetration into agar substrates, both species showed thermo-orientation, but only A. duodenale followed gradients of serum. The directing serum cues were not amino acids and glucose (the supposed cues for schistosome blood vessel localization), but Ringer's solution attracted the larvae. The host-finding and host-invasion behaviour of both hookworm species is well adapted to the invasion of the human skin, and there seems to be no particular adaptation of A. duodenale behaviour to the oral infection mode. Hookworm host-finding behaviour is not as complex as that of schistosome cercariae but seems well adapted to the ecological conditions in the transmission sites.

Ancylostoma↗

PubMed1988

Enzyme-linked immunosorbent assay using excretory/secretory and somatic antigens as a diagnostic test for human hookworm infection.

Excretory/secretory (E/S) and somatic antigens prepared from third stage infective larvae of Ancylostoma duodenale were evaluated for the diagnosis of human hookworm infection by enzyme-linked immunosorbent assay (ELISA). Taking the mean absorbance plus 2 standard deviations (SD) of normal serum as the cut-off value, the positivity rates in 30 hookworm cases were 97% and 93% respectively. False positivity with E/S antigen was 8-20% in 61 control subjects; with somatic antigen it was slightly lower. In contrast, when the mean absorbance value plus 2 SD of control groups with other parasitic infections was taken as cut-off point, the positivity was 93% with E/S antigen and 43% with somatic antigen, indicating the superiority of E/S antigen. Percentage positivity declined after treatment of hookworm cases. No relationship was found between ELISA reactivity and severity of infection.

Adolescent↗

PubMed1987

Do hookworms elicit protective immunity in man?

The two main species of human hookworm, Ancylostoma duodenale and Necator americanus (Table 1), are together believed to infect about 900 million people - mainly in tropical countries where adequate sanitary facilities may be lacking. But interactions between the two species, and their relative contributions to observed age-related infection patterns and seasonal cycles of transmission, continue to engender controversy. People tend to remain susceptible to infection through-out life, even with constant exposure to the infective stages. So what role does human immunity or resistance play in the epidemiology and control of infection? In this article, Jerzy Behnke reviews the epidemiology of hookworm infection in the light of current understanding of mechanisms involved in host responses to infection and hookworm evasion of those responses. As he stresses, much further work is required.

Journal Article↗

PubMed2006

Molecular cloning and characterization of a C-type lectin from Ancylostoma ceylanicum: evidence for a role in hookworm reproductive physiology.

Lectins comprise a family of related proteins that mediate essential cell functions through binding to carbohydrates. Within this protein family, C-type lectins are defined by the requirement of calcium for optimal biologic activity. Using reverse transcription PCR, a cDNA corresponding to a putative C-type lectin has been amplified from the hookworm parasite Ancylostoma ceylanicum. The 550 nucleotide open reading frame of the A. ceylanicum C-type Lectin-1 (AceCTL-1) cDNA corresponds to a 167 amino acid mature protein (18,706 Da) preceded by a 17 amino acid secretory signal sequence. The recombinant protein (rAceCTL-1) was expressed in Drosophila S2 cells and purified using a combination of affinity chromatography and reverse phase HPLC. Using in vitro carbohydrate binding studies, it was determined that rAceCTL-1 binds N-acetyl-d-glucosamine, a common component of eukaryotic egg cell membranes. Using a polyclonal IgG raised against the recombinant protein, the native AceCTL-1 was identified in sperm and soluble protein extracts of adult male A. ceylanicum by immunoblot. Probing of adult hookworm sections with the polyclonal IgG demonstrated localization to the testes in males, as well as the spermatheca and developing embryos in females, consistent with its role as a sperm protein. Together, these data strongly suggest that AceCTL-1 is a male gender-specific C-type lectin with a function in hookworm reproductive physiology.

Amino Acid Sequence↗

PubMed2006

Intestinal allergy expels hookworms: seeing is believing.

It is unclear how immunity limits hookworm infection. Australian researchers, using capsule and conventional gastrointestinal endoscopy in volunteers inoculated with Necator americanus, have reported that virtually all larvae reach the intestine within six weeks. Unlike the neutral response surrounding resident hookworms, newly arrived adults provoke an eosinophilic enteropathy. This allergic reaction curtails the attachment of hookworms and accompanies the passage of additional worms as they are expelled from the proximal small intestine.

Animals↗

PubMed1996

Genetic markers in ribosomal DNA for hookworm identification.

Polymerase chain reaction-linked restriction fragment length polymorphism (PCR-RFLP) analysis of ribosomal (r) DNA was conducted on Uncinaria stenocephala, Ancylostoma caninum, A. tubaeforme and A. ceylanicum. The rDNA region spanning the first and second internal transcribed spacers (ITS1 and ITS2) plus the 5.8S (ITS+) gene was amplified by PCR from each of the species, digested separately with 9 restriction endonucleases and the fragments separated by agarose gel electrophoresis. Characteristic PCR-RFLP patterns were produced for each morphologically defined species using some of the endonucleases. The present study demonstrated that the ITS+ provides genetic markers for the delineation of each species examined and suggests that this region of rDNA will be useful for the identification of other hookworms from a range of hosts. The results are likely to have important implications for studying the genetic structure of hookworm populations, the systematics and the epidemiology of hookworm infections.

Ancylostomatoidea↗

PubMed2003

Ac-FAR-1, a 20 kDa fatty acid- and retinol-binding protein secreted by adult Ancylostoma caninum hookworms: gene transcription pattern, ligand binding properties and structural characterisation.

Antibody against adult Ancylostoma caninum excretory-secretory (ES) products was used to immunoscreen a cDNA expression library leading to the isolation of cDNAs encoding putative hookworm fatty-acid and retinol-binding proteins. Ac-far-1 and Ac-far-2 cDNAs encode open reading frames corresponding to approximately 20kDa proteins with 91 percent amino acid identity. Ac-FAR-1 and Ac-FAR-2 exhibit clear similarities to other FARs of parasitic nematodes, most closely to two of the FAR proteins of Caenorhabditis elegans (Ce-FAR-1 and Ce-FAR-2). By reverse transcriptase polymerase chain reaction (RT-PCR) assay, Ac-far-1 mRNA was detected in both adult and third-stage larvae of A. caninum. However, the respective proteins were detectable by immunoblot only in adult hookworm ES products and adult extracts. Using fluorescence-based binding assays, bacterial recombinant Ac-FAR-1 was found to bind fatty acids and retinol (Vitamin A) with dissociation constants in the micromolar region. Circular dichroism spectra indicated that Ac-FAR-1 possesses a high level of alpha-helix, similar to Ov-FAR-1 from Onchocerca volvulus. This is the first demonstration of a functional FAR secreted by adult hookworms and provides further evidence that FAR proteins secreted by parasitic nematodes are crucial to parasitism.

Amino Acid Sequence↗

PubMed1998

A mutation scanning approach for the identification of hookworm species and analysis of population variation.

To overcome limitations in the morphological identification of different developmental stages of hookworms to species, we have established a polymerase chain reaction-linked single strand conformation polymorphism technique (PCR-SSCP) utilizing the internal transcribed spacers (ITS) of ribosomal (r)DNA. These spacers were specifically chosen because they provide reliable species markers for strongylid nematodes. ITS spacers were amplified by PCR from DNA derived from individual parasites of seven species of hookworm, then denatured and subjected to electrophoresis in a mutation detection enhancement (MDE) (non-denaturing) gel matrix. PCR SSCP analysis showed that the single-strand ITS patterns produced allowed the unequivocal identification of all species. The method also allowed the direct display of sequence variation within some species where multiple individual worms were examined. These findings demonstrate the usefulness of the SSCP approach for hookworm identification, the detection of population variation and the direct display of sequence variation in rDNA.

Ancylostomatoidea↗

PubMed1998

Hookworm-provoked IgE-mediated Pathology: Capricious Damage or Remarkable Strategy?

The existence of the canine hookworm Ancylostoma caninum in the human gut seems to be curtailed by an effective IgE-mediated inflammatory response against the helminth's feeding secretions, which, by damaging the host, compromises the parasite's feeding opportunities. In contrast, immunity does not develop against adapted, anthropophilic hookworm species, and it is suggested this relates to modulation of the inflammatory response by hookworm secretions. Here, John Croese discusses this hypothesis and its implications for the development of drugs to suppress allergy.

Journal Article↗

PubMed2006

A case of mistaken identity--reappraisal of the species of canid and felid hookworms (Ancylostoma) present in Australia and India.

This study serves to clarify the current status of canid and felid Ancylostoma species present in Australia. The morphological identification of A. ceylanicum from cats for the first time in Townsville, Australia, appears to be in error, together with the genetic markers provided for the species. Morphological and genetic data presented herein provide strong evidence that the hookworms from cats in Towsville are not A. ceylanicum as previously identified (i.e. the first report of this species in Australia), but are A. braziliense. Therefore the subsequent genetic markers established for A. ceylanicum in subsequent molecular studies based on these Townsville specimens should also be attributed to A. braziliense. Based on this information, a study of canine hookworm species present in northern India is also in error and it is apparent that the hookworms found in this region are those of A. ceylanicum. The distribution of A. braziliense and A. ceylanicum in the Americas and Asia Pacific region is discussed together with the importance of combining parasite morphology with genetic data for parasite diagnosis in epidemiological studies.

Ancylostoma↗

PubMed2000

A survey of genes expressed in adults of the human hookworm, Necator americanus.

Hookworms are gut-dwelling, blood-feeding nematodes that infect hundreds of millions of people, particularly in the tropics. As part of a program aiming to define novel drug targets and vaccine candidates for human parasitic nematodes, genes expressed in adults of the human hookworm Necator americanus were surveyed by the expressed sequence tag approach. In total 161 new hookworm genes were identified. For the majority of these, a function could be assigned by homology. The dataset includes proteases, protease inhibitors, a lipid binding protein, C-type lectins, an anti-bacterial factor, globins and other genes of interest from a drug or vaccine development viewpoint. Three different classes of small, secreted proteins were identified that may be involved in the host-parasite interaction, including potential potassium channel blocking peptides. One third of the genes were novel. These included highly expressed, secreted (glyco)proteins which may be part of the excretory-secretory products of these important pathogens. Of particular interest are a family of 9 genes with similarity to the immunomodulatory protein, neutrophil inhibitory factor, that may play a role in establishing an immunocompromised niche for this successful parasite.

Amino Acid Sequence↗

PubMed2002

Na-ctl-2, a cDNA encoding a C-type lectin expressed exclusively in adult Necator americanus hookworms.

C-type lectins (C-TLs) are carbohydrate-binding proteins central to diverse physiological processes including immunity, venom-induced haemostasis and wound repair. Here we describe the cloning of Na-ctl-2, a cDNA encoding a secreted C-TL from the human hookworm Necator americanus. The transcript was detected in mRNA from adult worms but not infective larvae. The cDNA encoded an N-terminal secretory signal peptide followed by a long-form C-TL domain with sequence similarity to C-TL-like proteins from Caenorhabditis elegans and mammalian antigen presenting cell receptors, suggesting that hookworms might utilise this class of lectin to interrupt anti-parasite immune responses or interfere with host clotting mechanisms. This is the first report of a full-length cDNA encoding a lectin from hookworms. The unusually skewed representation of this protein family within different nematode genera and its subsequent impact on the evolution of nematode parasitism is discussed.

Amino Acid Sequence↗

PubMed2003

Hookworm aspartic protease, Na-APR-2, cleaves human hemoglobin and serum proteins in a host-specific fashion.

Hookworms are voracious blood-feeders. The cloning and functional expression of an aspartic protease, Na-APR-2, from the human hookworm Necator americanus are described here. Na-APR-2 is more similar to a family of nematode-specific, aspartic proteases than it is to cathepsin D or pepsin, and the term "nemepsins" for members of this family of nematode-specific hydrolases is proposed. Na-apr-2 mRNA was detected in blood-feeding, developmental stages only of N. americanus, and the protease was expressed in the intestinal lumen, amphids, and excretory glands. Recombinant Na-APR-2 cleaved human hemoglobin (Hb) and serum proteins almost twice as efficiently as the orthologous substrates from the nonpermissive dog host. Moreover, only 25% of the Na-APR-2 cleavage sites within human Hb were shared with those generated by the related N. americanus cathepsin D, Na-APR-1. Antiserum against Na-APR-2 inhibited migration of 50% of third-stage N. americanus larvae through skin, which suggests that aspartic proteases might be effective vaccines against human hookworm disease.

Amino Acid Sequence↗

PubMed1986

Changes in the structural and functional properties of human eosinophils during experimental hookworm infection.

Normal volunteers were infected with hookworm larvae Necator americanus. Peripheral blood counts showed a mean of 524 +/- 29 eosinophils/mm3 of blood before infection and a mean of 3,008 +/- 456 eosinophils/mm3 of blood during infection (P less than .01). Absolute numbers of neutrophils did not change. Eosinophils and neutrophils from the infected period were compared with the noninfected state in each subject. The percentage of hypodense eosinophils increased from a mean of 34% +/- 13% to 80% +/- 7% during infection (P less than .05). Superoxide production of eosinophils increased from a mean of 56 +/- 9 to 97 +/- 12 nmol of O2-./10(6) cells per 60 min (P less than .05) during infection. Chemotaxis of eosinophils to Escherichia coli endotoxin-activated serum increased from a mean average distance migrated of 19 +/- 2 micron (P less than .05), whereas neutrophil responsiveness did not change. This is the first report of changes in eosinophil density and stimulation of eosinophil function in normal hosts experimentally infected with hookworm. The data indicate that hookworm infection preferentially increases eosinophil production and activity with little effect on neutrophils.

Chemotaxis, Leukocyte↗

PubMed1993

Ancylostoma factor Xa inhibitor: partial purification and its identification as a major hookworm-derived anticoagulant in vitro.

Soluble protein extracts from adult Ancylostoma hookworms were found to contain an anticoagulant activity that markedly prolonged both the prothrombin time (PT) and partial thromboplastin time (PTT). By chromogenic peptide substrate and clotting time assays, the anticoagulant activity was attributed to a specific inhibitor of clotting factor Xa. The hookworm anticoagulant was partially purified by ion-exchange column chromatography. Those column fractions containing anti-Xa activity by chromogenic assay also prolonged the PT and PTT as well as the factor X (Stypven) clotting time. These data suggest that this potent factor Xa inhibitor is a major anticoagulant from the adult Ancylostoma hookworm.

Ancylostoma↗

PubMed2004

Purification and molecular cloning of and immunization with Ancylostoma ceylanicum excretory-secretory protein 2, an immunoreactive protein produced by adult hookworms.

Hookworms remain major agents of global morbidity, and vaccination against these bloodfeeding parasites may be an attractive complement to conventional control methods. Here we describe the cloning of Ancylostoma ceylanicum excretory-secretory protein 2 (AceES-2), a novel immunoreactive protein produced by adult worms. Native AceES-2 was purified from excretory-secretory (ES) products by reverse-phase high-pressure liquid chromatography, subjected to amino-terminal sequencing, and cloned from adult worm RNA by using reverse transcription-PCR. The translated AceES-2 cDNA predicts that the mature protein consists of 102 amino acids and has a molecular mass of 11.66 kDa. Western immunoblot and enzyme-linked immunosorbent assay analyses demonstrated that recombinant AceES-2 (rAceES-2) reacted strongly with antibodies from A. ceylanicum-infected hamsters. Immunization of hamsters with native ES products adsorbed to alum induced antibodies that recognized rAceES-2, while rAceES-2-alum vaccination resulted in antibodies that reacted with a single protein band in ES products that closely approximated the size predicted for the native molecule. Infected hamsters that were passively immunized with hyperimmune rabbit anti-rAceES-2 serum exhibited more rapid and complete recovery from anemia than controls that received normal serum. Oral immunization with rAceES-2 was associated with significantly reduced anemia upon challenge, an outcome similar to the outcome observed in hamsters that were orally vaccinated with soluble hookworm extract (the latter animals were also resistant to weight loss). These data suggest that AceES-2 plays an important role in the host-parasite interaction and that vaccination against this protein may represent a useful strategy for controlling hookworm anemia.

Administration, Oral↗

PubMed2005

Biochemical characterization and vaccine potential of a heme-binding glutathione transferase from the adult hookworm Ancylostoma caninum.

We report the cloning and expression of Ac-GST-1, a novel glutathione S-transferase from the adult hookworm Ancylostoma caninum, and its possible role in parasite blood feeding and as a vaccine target. The predicted Ac-GST-1 open reading frame contains 207 amino acids (mass, 24 kDa) and exhibited up to 65% amino acid identity with other nematode GSTs. mRNA encoding Ac-GST-1 was detected in adults, eggs, and larval stages, but the protein was detected only in adult hookworm somatic extracts and excretory/secretory products. Using antiserum to the recombinant protein, Ac-GST-1 was immunolocalized to the parasite hypodermis and muscle tissue and weakly to the intestine. Recombinant Ac-GST-1 was enzymatically active, as determined by conjugation of glutathione to a model substrate, and exhibited a novel high-affinity binding site for hematin. The possible role of Ac-GST-1 in parasite heme detoxification during hemoglobin digestion or heme uptake prompted interest in evaluating it as a potential vaccine antigen. Vaccination of dogs with Ac-GST-1 resulted in a 39.4% reduction in the mean worm burden and 32.3% reduction in egg counts compared to control dogs following larval challenge, although the reductions were not statistically significant. However, hamsters vaccinated with Ac-GST-1 exhibited statistically significant worm reduction (53.7%) following challenge with heterologous Necator americanus larvae. These studies suggest that Ac-GST-1 is a possible drug and vaccine target for hookworm infection.

Amino Acid Sequence↗