A. J. C. Fulford

Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non‐obese diabetic mice

The spontaneous development of insulin dependent diabetes mellitus in non‐obese diabetic (NOD) mice has been shown to be mediated by a Th1 response against beta cell antigens. It is known that in murine models of Schistosoma mansoni infection, egg production is associated with a switch from a Th1 to Th2 response. This subsequent dominance of a Th2 response in S.mansoni infected mice has been shown to influence the response to other infectious agents or antigens. We therefore determined whether infection with S.mansoni could influence the spontaneous incidence of insulin dependent diabetes mellitus (IDDM) in NOD mice. Infection with this helminth significantly reduced the spontaneous incidence of IDDM. IDDM was also prevented by injecting parasite eggs alone. Because until relatively recently humans might expect to succumb to a variety of infectious agents, the current freedom from infection might permit the expression of a genetic predisposition to autoimmune pathology and be responsible for the increased incidence of IDDM.

Adult resistance to schistosomiasis mansoni: age-dependence of reinfection remains constant in communities with diverse exposure patterns.

In a fishing community on Lake Albert in Uganda the pattern of intensity of Schistosoma mansoni infection 6 months after treatment with praziquantel was found to be very similar to reinfection patterns seen in previously studied endemic communities: the profile peaks sharply at around the age of 10 years falling away rapidly to much lower levels in adults. This is in stark contrast to the patterns of water contact, which differ greatly between fishing and non-fishing communities. On Lake Albert, adults appear to be more heavily exposed than children. From these observations we conclude that adults are physiologically (perhaps immunologically) more resistant to infection after treatment than children.

Puberty and Age-related Changes in Susceptibility to Schistosome Infection.

Recent data from outbreaks of schistosomiasis in immunologically naive populations have refuelled the debate concerning the nature or existence of protective, acquired immunity to schistosomiasis in humans. Data from endemic communities provide some compelling evidence for an abrupt change in reinfection rates that coincides with puberty. We suggest that the hormonal changes of adrenarche may hold the key to understanding the relative resistance to infection found in adults.

A statistical approach to schistosome population dynamics and estimation of the life-span of Schistosoma mansoni in man

Dynamic models which predict changes in the intensity of schistosome infection with host age are fitted to pre-intervention Schistosoma mansoni data from Kenya. Age-specific post-treatment-reinfection data are used to estimate the force of infection, thus enabling investigation of the rate of worm death. An empirical and statistical approach is taken to the model fitting: where possible, distributional properties and function relationships are obtained from the data rather than assumed from theory. Attempts are made to remove known sources of bias. Maximum likelihood techniques, employed to allow for error in both the pre-intervention and reinfection data, yield confidence intervals for the worm life-span (CI95% = 5.7-10.5 years) and demonstrate that the worm death rate is unlikely to vary with host age. The possibilities and limitations of fitting dynamic models to data are discussed. We conclude that a detailed, quantitative approach will be necessary if progress is to be made with the interpretation of epidemiological data and the models intended to describe them.

Comparison of different chemotherapy strategies against Schistosoma mansoni in Machakos District, Kenya : effects on human infection and morbidity

A comparison was made of the long-term impact of different methods of administration of chemotherapy (oxamniquine, 30 mg/kg in divided doses; or praziquantel, 40 mg/kg) on prevalence and intensity of Schistosoma mansoni infection in four areas in Kangundo Location, Machakos District, Kenya. In Area A, treatment was offered in October 1983 and again in April 1985 to all infected individuals. In Area H, treatment was offered in April 1985 to individuals excreting greater than or equal to 100 eggs per gram (epg) of faeces. In Area S, treatment was offered in April 1985 to all infected school children, within the framework of the primary schools. In the witness area, Area W, treatment was given in April 1985, for ethical reasons, to a small number of individuals excreting greater than or equal to 800 epg. Prevalence and intensities of infection were subsequently monitored at yearly intervals for three complete post-treatment years. In the Area S schools, clinical examination was also carried out at yearly intervals. Treatment of all infected individuals on two occasions (Area A) was the most effective and long-lasting way of reducing prevalence and intensity of infection. In this area, however, some earlier interventions had been carried out and pre-treatment intensities were lower than in the other areas. Treatment only of infected schoolchildren (Area S) also had a marked and prolonged effect, comparable to or better than treatment of individuals with heavy infections (Area H). Treatment of infected schoolchildren also caused a persistent reduction in the prevalence of hepatomegaly, and there was suggestive evidence from intensities of infection in community stool surveys (but not from incidence rates) of an effect on transmission. In all study areas, reinfection was most rapid and most intense among children. These findings are discussed in the light of theoretical considerations and of results from other studies, both on schistosomiasis and on intestinal helminths. We conclude that, in areas of low morbidity such as Kangundo, chemotherapy of schoolchildren only, at intervals of up to 3 years, is a satisfactory way of producing a long-term reduction in both intensity of infection and morbidity.

Increases in human T helper 2 cytokine responses to Schistosoma mansoni worm and worm-tegument antigens are induced by treatment with praziquantel.

Levels of Schistosoma mansoni-induced interleukin (IL)-4 and IL-5 and posttreatment levels of immunoglobulin E recognizing the parasites tegument (Teg) correlate with human resistance to subsequent reinfection after treatment. We measured changes in whole-blood cytokine production in response to soluble egg antigen (SEA), soluble worm antigen (SWA), or Teg after treatment with praziquantel (PZQ) in a cohort of 187 individuals living near Lake Albert, Uganda. Levels of SWA-induced IL-4, IL-5, IL-10, and IL-13 increased after treatment with PZQ, and the greatest relative increases were seen in the responses to Teg. Mean levels of Teg-specific IL-5 and IL-10 increased ~10-15-fold, and mean levels of IL-13 increased ~5-fold. Correlations between the changes in cytokines suggested that their production was positively coregulated by tegumentally derived antigens. Levels of SEA-, SWA-, and Teg-induced interferon- gamma were not significantly changed by treatment, and, with the exception of IL-10, which increased slightly, responses to SEA also remained largely unchanged. The changes in cytokines were not strongly influenced by age or intensity of infection and were not accompanied by corresponding increases in the numbers of circulating eosinophils or lymphocytes.

On the use of age-intensity data to detect immunity to parasitic infections, with special reference to Schistosoma mansoni in Kenya

We consider two phenomena, related to the host age-intensity profiles of parasitic infections, which have been suggested to be indicative of acquired immunity: (i) a lower age of peak intensity among more intensely infected hosts; and (ii) a decline with age in the dispersion of the distribution of parasites between hosts. We demonstrate that these phenomena occur among Kenyan schoolchildren infected with Schistosoma mansoni, although the magnitude of both is small. We also examine the mathematical models underlying these predictions and conclude that both phenomena are possible in the absence of acquired immunity or, indeed, in the absence of any density-dependent effect. In our opinion, insufficient attention has been focused upon mathematical models, describing the null hypothesis, i.e. density-independent models. In particular, we regard the usual assumptions made for the two stochastic components of these models, describing the heterogeneity between hosts and the probabilistic nature of infection and death of parasites, as too rigid and unrealistic. We demonstrate that deviation from these assumptions undermines the qualitative distinctions between models which describe acquired immunity or density dependence and those which are density-independent.

Analysis of Complex Patterns of Human Exposure and Immunity to Schistosomiasis mansoni: The Influence of Age, Sex, Ethnicity and IgE

Background Numerous factors may influence Schistosoma infection intensity and prevalence within endemic communities, including exposure-related factors such as local environment and behaviour, and factors relating to susceptibility to infection such as immunology and genetics. While animal studies performed in the laboratory can be tightly controlled, human populations are highly heterogeneous, varying according to demographic characteristics, genetic background and exposure to infection. The heterogeneous nature of human water contact behaviour in particular makes it difficult to distinguish between a lack of cercarial exposure and reduced susceptibility to infection as the cause for low levels of infection in the field. Methods and Principal Findings In this study we investigate risk factors for Schistosoma mansoni infection in a rural Ugandan fishing community receiving treatment as part of a multi-disciplinary longitudinal reinfection study. More specifically, we examine the influence that age, sex and ethnic background have on susceptibility to reinfection after anti-helminth drug treatment, but use individual estimates of cercarial exposure and multivariable methods in an attempt to remove noise created by environmental and behavioural heterogeneities. We then investigate whether schistosome-specific IgE immune responses could account for any remaining variations in susceptibility to reinfection. Our findings suggest that observed ethnic- and sex-related variations in S. mansoni reinfection were due to variations in cercarial exposure, as opposed to biological differences in susceptibility to infection. Age-related differences in reinfection were not explained by exposure, however, and appeared linked to the balance of IgE and IgG4 to the tegumental antigen SmTAL1 (formerly Sm22.6), which itself was significantly related to resistance to reinfection. Conclusions This study highlights the benefit of taking a multidisciplinary approach in complex field settings; it allows the ecology of a population to be understood and thus more robust conclusions to be made.

The development of an age structured model for schistosomiasis transmission dynamics and control and its validation for Schistosoma mansoni.

Mathematical models are potentially useful tools to aid in the design of control programmes for parasitic diseases. In this paper, a fully age structured epidemiological model of human schistosomiasis is developed and parameterized, and used to predict trends in infection prevalence, intensity and prevalence of heavy infections over age and time during several rounds of mass and age targeted treatment. The model is validated against data from a Schistosoma mansoni control programme in Kenya.

The influence of sex and age on antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum in human populations in Kenya and the Philippines

We have investigated the effects of host age and sex on human antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum adult worm (AW) and soluble egg (SEA) antigens, using sera from subjects in Kenya and the Philippines. Similar trends with age were observed between the two populations despite host, parasite and environmental differences between the two geographical locations. IgE to AW increased with age, whereas most isotype responses to SEA decreased with age. IgG1, IgG3 and IgG4 subclass responses to adult worm, however, did not show a broadly rising or falling pattern with age. Males were found to have higher IgG1, IgG4 and IgE to AW in both populations. This sex difference remained significant in the Kenyan population even after controlling statistically for confounding factors such as age and differences in intensity of infection. Analysis of S. mansoni and S. japonicum adult worm antigens reactive with IgE revealed a predominant 22 kDa band in both parasites. Only those individuals with relatively high IgE titres specifically reactive with S. mansoni or S. japonicum AW had detectable IgE against Sj22 or Sm22.