Intestinal Absorption Tests and Biopsy of the Jejunum in Subjects with Heavy Hookworm Infection *

Layrisse, Miguel; Blumenfeld, Norma; Carbonell, Luis F.; Desenne, Jean J.; Roche, Marcel

doi:10.4269/ajtmh.1964.13.297

Cited by 52 publications

(18 citation statements)

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“…Such a strategy potentially allows the worm to avoid substantial proteolytic damage while feeding on the submucosa. However, a secondary effect of AceKI might be impairment of host nutrient absorption through the inhibition of pancreatic enzymes, thus lending further credence to Darke's original yet somewhat controversial hypothesis (45,64). In light of the accumulating evidence that malnutrition is associated with increased susceptibility to infection by a variety of pathogens, the presence of a chronic malnourished state could potentially favor repeated infection with soil-transmitted helminths, including hookworms (3,17,38,40,50,59,63).…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization ofAncylostoma ceylanicumKunitz-Type Serine Protease Inhibitor: Evidence for a Role in Hookworm-Associated Growth Delay

Chu¹,

Bungiro²,

Ibanez³

et al. 2004

Infect Immun

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Hookworm infection is a major cause of iron deficiency anemia and malnutrition in developing countries. The Ancylostoma ceylanicum Kunitz-type inhibitor (AceKI) is a 7.9-kDa broad-spectrum inhibitor of trypsin, chymotrypsin, and pancreatic elastase that has previously been isolated from adult hookworms. Site-directed mutagenesis of the predicted P1 inhibitory reactive site amino acid confirmed the role of Met 26 in mediating inhibition of the three target serine proteases. By using reverse transcription-PCR, it was demonstrated that the level of AceKI gene expression increased following activation of third-stage larvae with serum and that the highest level of expression was reached in the adult stage of the parasite. Immunohistochemistry studies performed with polyclonal immunoglobulin G raised against recombinant AceKI showed that the inhibitor localized to the subcuticle of the adult hookworm, suggesting that it has a potential in vivo role in neutralizing intestinal proteases at the surface of the parasite. Immunization with recombinant AceKI was shown to confer partial protection against hookworm-associated growth delay without a measurable effect on anemia. Taken together, the data suggest that AceKI plays a role in the pathogenesis of hookworm-associated malnutrition and growth delay, perhaps through inhibition of nutrient absorption in infected hosts.Hookworm infection remains a major global health problem, and over one billion people are reportedly infected in developing countries (9, 14). Hookworms, which are bloodfeeding intestinal nematodes, are a major cause of iron deficiency anemia and malnutrition (15,20,(59)(60)(61)64). While the anemia is presumably due to the cumulative effect of chronic intestinal blood loss, the molecular mechanisms underlying the pathogenesis of hookworm malnutrition remain unknown. Although it has been suggested that hookworm malnutrition and growth delay occur secondary to chronic iron deficiency, particularly in children, evidence from prior clinical studies suggests that hookworm infection is also associated with various degrees of intestinal malabsorption (18,35,54,57,62). It has been hypothesized that this hookworm malabsorption syndrome might occur secondary to mucosal inflammation triggered by the adult worm attached to the intestinal epithelium or might be a result of secretion of parasite inhibitors of host digestive enzymes (18).As part of a series of ongoing studies aimed at characterizing adult hookworm secretory proteins, a cDNA corresponding to the gene encoding a putative Kunitz-type serine protease inhibitor was previously identified from adult Ancylostoma ceylanicum RNA by using a PCR-based approach (48). The A. ceylanicum Kunitz-type inhibitor (AceKI) cDNA was expressed in Escherichia coli, and the recombinant protein was found to inhibit the pancreatic enzymes chymotrypsin, pancreatic elastase, and trypsin in vitro, with equilibrium inhibitory dissociation constant (K i ) values ranging from picomolar levels to low nanomolar levels. The native AceKI prote...

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Section: Discussionmentioning

confidence: 99%

Molecular Characterization ofAncylostoma ceylanicumKunitz-Type Serine Protease Inhibitor: Evidence for a Role in Hookworm-Associated Growth Delay

Chu¹,

Bungiro²,

Ibanez³

et al. 2004

Infect Immun

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“…They also have a marked effect on intestinal morphology, which has been attributed both to the biting activities of adult worms and to the accompanying host response (Alkazmi et al, 2006). Much of the evidence for inflammatory cellular infiltration into the human intestinal mucosa during hookworm infection comes from case studies and endoscopically derived samples obtained from hospitalized subjects, often conducted with a view to assessing effects of infection on absorption of nutrients rather than specifically to assess the nature of the inflammation itself (Layrisse et al, 1964;Aziz & Siddiqui, 1968). These studies indicate that goblet cell hyperplasia is frequently, but not invariably, found in hookworm infections, as are focal accumulations of eosinophils (Chaudhuri & Saha, 1964).…”

Section: Introductionmentioning

confidence: 99%

The mucosal cellular response to infection withAncylostoma ceylanicum

2008

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Although hookworms are known to stimulate inflammatory responses in the intestinal mucosa of their hosts, there is little quantitative data on this aspect of infection. Here we report the results of experiments conducted in hamsters infected with Ancylostoma ceylanicum. Infection resulted in a marked increase in goblet cells in the intestinal mucosa, which was dependent on the number of adult worms present and was sustained as long as worms persisted (over 63 days) but returned to baseline levels within 7 days of the removal of worms by treatment with ivermectin. Increased mast cell responses were also recorded. Levels were again dependent on the intensity of worm burdens and lasted as long as 63 days after infection. When worms were eliminated, mast cell numbers took over 2 weeks to return to normal. Paneth cell numbers fell soon after infection, the degree of reduction being dependent on the worm burden. After clearance of worms, Paneth cell numbers returned to normal within a week, but then rebounded and numbers rose to higher levels than those in control naïve animals. The time course of the response was similar whether animals experienced a chronic low-intensity infection without loss of worms or a higher intensity infection during the course of which worm burdens were gradually reduced. Clearly, A. ceylanicum was able to induce a marked inflammatory response in its host's intestine which was sustained for over 9 weeks after infection, and which hamsters appeared able to tolerate well. Our data draw attention to the resilience of hookworms which, unlike many other nematodes, are able to survive for many weeks in a highly inflamed intestinal tract.

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“…It has been claimed that infestation with hookworm may cause morpho logical changes in the intestine [Sheehy et al, 1962;Tandon et al, 1966;Chuttani et al, 1967], However, the evidence is conflicting [Layrisse et al, 1964;Burman et al, 1970] and further controlled studies are needed in this area. Infestation with other parasites such as Strongyloides stercoralis [Stemmermann, 1967], Giardia lamblia [Yardley et al, 1964] and Capillaria philipenensis [Whalen et al, 1969] may cause changes in the intestinal mucosa, but the distribution of these parasites is not suf ficiently ubiquitous to be responsible for the observed abnormalities.…”

Section: A Etiologymentioning

confidence: 90%

Geographical Variations in the Morphology of the Small Intestinal Mucosa in Apparently Healthy Individuals

Baker¹

1973

Pathobiology

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Macroscopic and microscopic photographs of seven jejunal biopsies illustrating the range of morphological changes found in southern Indian control subjects were circulated, together with a questionaire, to observers in different parts of the world. There was general agreement among the observers regarding the ‘normality’ of the biopsy showing the least changes and the abnormality of the two showing the most marked changes, but considerable disagreement over those intermediate between these two extremes. Opinion regarding the prevalence of the different biopsy appearances in control subjects varied significantly between temperate and tropical areas. A hierarchy of abnormality has been drawn up ranking countries in decreasing order of prevalence of the two most abnormal biopsies. Possible factors in the pathogenesis of the morphological changes in the jejunal mucosa in the tropics are discussed.

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Intestinal Absorption Tests and Biopsy of the Jejunum in Subjects with Heavy Hookworm Infection *

Cited by 52 publications

References 0 publications

Molecular Characterization ofAncylostoma ceylanicumKunitz-Type Serine Protease Inhibitor: Evidence for a Role in Hookworm-Associated Growth Delay

Molecular Characterization ofAncylostoma ceylanicumKunitz-Type Serine Protease Inhibitor: Evidence for a Role in Hookworm-Associated Growth Delay

The mucosal cellular response to infection withAncylostoma ceylanicum

Geographical Variations in the Morphology of the Small Intestinal Mucosa in Apparently Healthy Individuals

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