The organism and its antigens

Ascaris lumbricoides is among the most widespread and common of all pathogens of humans, infecting over 1.3 billion people. It is a nematode, or 'roundworm', and can arguably present the human host with a greater burden of foreign biological material than does any other parasite. Sexually-producing adult worms develop in the intestine to a maximum size of about 400 mm long by 6 mm thick, and females release eggs at the rate of 200 000 per day. These take about 2-3 weeks to embryonate and produce the infective larvae. Following ingestion, the larvae emerge from the egg, invade the mucosa, migrate to the lungs via the liver, break out into the alveoli, move up the trachea and are swallowed. Upon re-entry to the intestine, they develop to mature adult worms, mate, and eggs usually begin to be released in the feces by about 60-70 days of infection.

It has often been written that the vast majority of ascariasis cases are symptomless, but it is becoming clear that chronic malabsorbtion and malnutrition can result, and even single worms can prove lethal by penetrating the bile or pancreatic ducts. Rupture and/or blockage of the intestine by the sheer mass of worms is estimated to kill about 20000 children a year, but this is almost certainly a gross underestimate. Treatment by anthelmintics is effective but parasite infections can return to pretreatment levels within 1 year because of contamination of the environment with the highly persistent eggs. There is, therefore, little evidence for the acquisition of a sterile immunity to the parasite in humans, although certain individuals appear to remain consistently uninfected. A characteristic of most helminthiases, including ascariasis, is that the parasite population is overdispersed within a host population. That is, most of the parasites are present in a small proportion of potential hosts, and the majority of people are parasite-free or have only small burdens. Among infected individuals, children tend to suffer infections of greater intensity than do those in older age groups. Recent genetic studies on the parasites have shown that the closely related parasite of pigs, A. suum, probably does not reach maturity in humans, but exposure to it might nevertheless influence the immune response to A. lumbricoides.

The first clinical signs of infection are associated with the pulmonary phase and include pneumonitis, cough, dyspnea, substernal pain and sometimes a blood-stained sputum. This is known as the Loffler syndrome and has some of the characteristics of an immediate-type hypersensitivity response. There can be a dense pulmonary infiltrate at this time, and a rising eosinophilia. Pulmonary hypersensitivity can cause significant mortality among children in arid regions where high-level seasonal transmission occurs. The intestinal phase is associated with digestive disorders, nausea and colic. Villous atrophy has been demonstrated in infected children and pigs, and is probably immune-associated.

Until recently, work on the antigens of Ascaris has been confined to somatic materials of the parasite. These have been shown to be rich in the phosphoryl-choline hapten, and antibody responses to it are a major part of the response to infection in mice. The determinant is found internally and is not thought to be exposed on the parasite surface. Ascaris is renowned among laboratory workers for its content of allergens, and proteinaceous allergens ranging between 14.4 and 360 kDa have been described. A nonspecific mast cell-degranulating factor of about 9 kDa has also been described from Ascaris. The extent to which these substances contribute to pathology is not clear, but there is one report of lethal intestinal anaphylaxis following chemotherapy for ascariasis, and it is likely that parasite allergens contribute to pulmonary hypersensitivity.

It is now clear, however, that antigens released by the tissue-invasive larvae of the parasite (usually termed 'excretory/secretory' (ES) products) are potently immunogenic and that the set of (glyco) proteins of which they are comprised changes radically during the migration from intestine to lungs. The larvae also release several proteinases, the biochemical activity of which are inhibitable by antibody elicited by the infection. ES products contain components ranging from 14 to 410 kDa, the 14 kDa component also being found in abundance internal to the worm, and is a potent allergen named ABA-1. This protein is now known to be a fatty acid and retinoid-binding protein which appears to have no homolog in vertebrates, and has highly unusual binding characteristics. It is thought to be a four-bundle a-helix protein with its binding site in its core (Figure 1). ABA-1 is a member of the nematode

Figure 1 Model of the ABA-1 allergen of Ascaris, showing the proposed four ct-helix bundle structure. The protein is known to form dimers and the position of putative external hydrophobic patches on helices 1 and 2, which may act as the subunit interface, are shown as black rectangles. (Courtesy of Dr A Brass, University of Manchester, UK.)

Figure 1 Model of the ABA-1 allergen of Ascaris, showing the proposed four ct-helix bundle structure. The protein is known to form dimers and the position of putative external hydrophobic patches on helices 1 and 2, which may act as the subunit interface, are shown as black rectangles. (Courtesy of Dr A Brass, University of Manchester, UK.)

polyprotein antigens/allergens which appear to be produced by all nematodes as a polyprotein that is cleaved by proteinases during post-translational processing into multiple copies of the active allergen protein.

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