In recent immuno-epidemiological studies, it was established that, in individuals who are treated with praziquantel after exposure to water contaminated with schistosome cercariae, resistance to reinfection by Schistosoma haematobium and Schistosoma mansoni depends on the age of the patient. Moreover, age-prevalence and age-intensity trends for S. haematobium and S. mansoni generally conform to a clear pattern, which is supported by more recent evidence. Results from these studies indicate that, although the frequency of water contact declines in older children and adults, this decline is not sufficient to account for the marked reduction with age in reinfection rates after treatment. Further, strong evidence has been compiled in recent years illustrating the acquisition of acquired immunity to schistosomiasis in humans infected with S. mansoni and S. haematobium. Preliminary studies on Schistosoma japonicum in China and the Philippines have noted associations suggesting acquired immunity.
In a Kenyan population, the involvement of eosinophil-mediated schistosomulum killing has been shown to be associated with resistance to S. mansoni and to be mediated by antibodies binding to the high-affinity IgE receptor on eosinophils. In contrast, the presence of IgM- and IgG4-blocking antibodies correlates inversely with protection. IgE appears to be related to resistance to reinfection after chemotherapy. More recently, some studies have shown that the protective effect of IgE is partly counterbalanced by the opposite action of IgG4; in particular, the high susceptibility of young individuals could be related to a shift in the IgE/IgG4 balance toward a greater effect of IgG4. Thus, the current view is that resistance depends partly on a balance between two antagonistic effects: the protective effect of IgE and the negative action of IgG4.
In addition, recent studies have shown that several schistosomal antigens and recombinant molecules (P28, 22-kDa protein, GST, Sj31/32) may play a role in inducing protective immune responses. Studies on the cellular and humoral components of such protective responses have allowed the demonstration and characterization of a range of possible effector mechanisms. In human schistosomiasis, clarification of strict protective versus pathological roles for Th1 and Th2 lymphocyte responses remains elusive. Immuno-epidemiological studies have implicated Th2-type responses in protection against reinfection with schistosomes. A recent study based in Brazil reports that the IgE and IgG4 response to defined S. mansoni antigens aggregates within families. Such findings reinforce other kinship and family studies of genetic susceptibility that have indicated the presence of a codominant major gene (SM1) controlling the intensity of S. mansoni infection. SM1 has been localizedto a region of chromosome 5 (5q31–q33) close to the gene encoding the colony stimulating factor-1 receptor (CSF1R) and others encoding cytokines or cytokine receptors implicated in the regulation of the immune response against schistosomiasis and other pathogens. Furthermore, there is evidence indicating that the SM1 locus controls the differentiation of Th2 lymphocytes and schistosome infection. No linkage studies of the susceptibility to infection have been undertaken on Asian schistosomiasis. We wish to pursue this area of research with the aim of determining whether a major gene is involved, as is the case of S. mansoni. Furthermore, we wish to investigate whether, as has been suggested for schistosomiasis caused by S. mansoni and other diseases resulting in abnormal fibrosis, polymorphisms within the IFN-γR1 gene (mapping to chromosome 6q22–q23), which encodes the receptor for the antifibrogenic cytokine interferon-γ,determine severe hepatic disease.
We recently completed field work on genetic susceptibility to S. japonicum and other helminth parasites in a population from the Poyang Lake region of China.We tested four models for each individual helminth infection: environmental, household, polygenic, and general (household and polygenic). All models incorporated village effects as well as age and sex. Ascaris infection analysis incorporated Trichuris infection and vice versa. Models for S. japonicum infection incorporated water contact as a covariate. We compared all models with each other using the likelihood ratio test. Trichuris infection was best described by the polygenic model. Heritability was strong (25.4%) and a significant (P<0.05) risk. We also detected a genetic effect for S. japonicum infection (29.6%) as well as a strong household component (18.8%). For Ascaris infection, a household model was favored indicating that 31.2% of the risk of infection is attributable to the domestic environment. We observed no clustering of infection at a familial level. This contradicts a previous study from another lab, probably due to a lack of power in that study to detect any genetic effects. Given the strong association observed between Ascaris and Trichuris infection, we undertook a variance components analysis to determine factors underlying the risk of having both infections concurrently. Both household and polygenic effects were strongly significant (P<0.05). Heritability was estimated to be 26.3% and household accounted for 49.37% of the risk of having a double infection. Using infection number as the phenotype, we investigated aggregation of general polyparasitism. This ranged from 0 (having no infection) to 3 (harboring all three parasites) and was treated as a continuous variable with a normal distribution. The variance components analysis estimated a heritability of 16.5% and a household effect of 8.4%. When we compared both household and polygenic models with the general model, genetic and shared environment effects remained significant in the presence of each other (P<0.05).
In conclusion, helminth infections appear to aggregate in families, possibly as a consequence of genetic factors. Multiple infections and polyparasitism are common and also appear to be controlled by genetic effects. This suggests that the genetic risk associated with infection with one helminth is not independent of another. The study provides the first insight into multiple parasite infections and polyparasitism. We have collected 589 saliva and blood samples and plan to extract DNA from the saliva samples and use it for further genetic association analyses.
Last updated September 2008
