Pathogenesis

The pathogenesis of disease differs in different hosts. In a definitive host such as the dog, infection of the adult intestine with Toxocara worms normally causes little disturbance or intestinal pathology. Infected puppies can exhibit intestinal pathology accompanied by poor growth, vomiting and diarrhoea, and death can occur when infections are very heavy (Lloyd, 1993).

Other species, such as mice and humans, can act as paratenic hosts in which the life-cycle halts at the larval stage and no adult worms develop to maturity within the host intestine. In this situation, the presence of migrating larvae within the tissues contributes to pathology that is dependent upon the intensity of infection and the location of the larvae. Two organs of particular concern that are known to be invaded by Toxocara larvae are the eye and the brain. Various aspects of ocular toxocariasis are discussed further in the sections on Epidemiology, Clinical Signs, Diagnosis and Treatment. Most of the pathology associated with this infection results from tissue damage caused by inflammatory responses induced by the presence of larvae and the activity of certain toxic products produced by the larvae themselves.

Larval invasion of the brain is common in mice and there is evidence that larvae accumulate in that organ (Dunsmore et al., 1983). The relationship between observed behavioural changes in infected murine hosts and the potential significance for humans is discussed in the Epidemiology section. A number of cases of infection of the human brain have been recorded in the literature (Hill et al., 1985). One particular case was reported from a child aged 2.5 years, killed by non-accidental injury (Hill et al., 1985). The child was said to have cried incessantly. Nematode larvae were found in the pons, right frontal lobe and white matter of the cerebellum and surrounded by a giant cell reaction.

Transplacental infection has not been recorded in humans. Kincekova et al. (1995) reported the detection of anti-Toxocara IgM antibody in seven out of 24 neonates born to IgG-seroposi-tive mothers suggesting that transplacental infection may have occurred. Taylor et al. (1996) studied maternal and cord blood sera. The cord blood sera were found to reflect maternal levels of total anti-Toxocara antibody. All positive cord blood samples were examined for IgM anti-Toxocara antibody but none was found, suggesting that reactivation of dormant larvae with subsequent transplacental infection of the foetus did not occur in this human study group. It was noted that there was a higher miscarriage rate in the Toxocara-positive mothers.

In contrast, evidence for transplacental infection in mice has been recorded by a number of authors (Lee et al., 1976; Hassan and El-Manawaty, 1994). Reduction in litter size has also been reported in Toxocara canis-infected mice (Akao et al., 1990).

Excretory-Secretory Antigens

Larvae of T. canis are known to survive for long periods of time in culture and to produce large amounts of excretory-secretory (ES) antigen (de Savigny, 1975). These properties have provided the opportunity for this system to be used to study the functional aspects of the ES antigen, and as a model for other tissue-invasive helminths that are less easily maintained under laboratory conditions (Maizels and Robertson, 1991).

Five major TES (Toxocara canis excreted-secreted antigens) macromolecules have been defined and are described as TES-32, TES-55, TES-70, TES-120 and TES-400 kDa (Maizels et al., 1984; Meighiji and Maizels, 1986; Maizels and Robertson, 1991). All the major TES products are glycosylated and there is evidence for O-linked sugars and proteoglycan-like polymers (Maizels et al., 1993). These glycoconjugates are rapidly recognised by the immune system and provoke strong antibody responses. There is no indication that these responses have a protective function and it has been suggested by Maizels and Robertson (1991) that one advantage of producing large quantities of ES antigen is to divert the immune system into the synthesis of ineffective antibody.

Toxocara larvae have been shown to be resistant to direct killing by eosinophils from guinea pigs (Badley et al., 1987) and humans (Fattah et al., 1986). Eosinophils adhere, activate and degranulate but the larvae show little sign of damage and indeed are able to slough off the cells, together with extracuticular material (Mai-zels and Robertson, 1991). The release of surface antigens may be additional to the normal turnover of surface antigens from the larval cuticle (Maizels et al., 1984; Smith et al., 1981). Evidence now suggests that the surface coat, containing some TES antigen, is formed to serve as a labile structure to be shed on attack by antibody or effector cells (Page et al., 1992). This ties in with the earlier suggestion by Smith et al. (1981) of a dynamic larval surface which, when bound by antibody, is sloughed off unless metabolically arrested. The extracuticular layer has been described as an electron-dense, fuzzy envelope 10 nm in thickness and detached from the epicuticle (Maizels and Selkirk, 1988; Maizels and Page, 1990). It has been termed the electron-dense layer of granular material (DGM), with similarities to a glycocalyx (Page et al., 1992). More recently, Maizels and colleagues have

Fig. 19a.2 Median absolute eosinophil counts in relation to Toxocara titre for (a) all subjects and (b) after exclusion of those with asthma, eczema or hay fever

extended this investigation of ES antigens to characterise two different presumptive ES/surface molecules, one an abundantly expressed mucin-like protein (Gems and Maizels, 1996) and the other a phosphatidyl ethanolamine-binding protein (Gems et al., 1995).

T. canis larvae produce an elastase-like protease that is capable of degrading extracellular matrix proteins (Robertson et al., 1989). It has been suggested that these secreted proteases are used by the larvae during tissue migration. In addition to these protective and other functions, the ES antigens on the surface of Toxocara larvae also contribute to pathogenesis. Antigen has been identified in circulating immune complexes (Bowman et al., 1987) and in the tissues of infected animals (Parsons et al., 1986). In chronic infections antigen was localised within granulomas as well as in 'verminous tracks' in the absence of larvae, a finding which suggests antigen shedding.

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