Shona Wilson

Epidemiology and control of human schistosomiasis in Tanzania

In Tanzania, the first cases of schistosomiasis were reported in the early 19th century. Since then, various studies have reported prevalences of up to 100% in some areas. However, for many years, there have been no sustainable control programmes and systematic data from observational and control studies are very limited in the public domain. To cover that gap, the present article reviews the epidemiology, malacology, morbidity, and the milestones the country has made in efforts to control schistosomiasis and discusses future control approaches. The available evidence indicates that, both urinary and intestinal schistosomiasis are still highly endemic in Tanzania and cause significant morbidity.Mass drug administration using praziquantel, currently used as a key intervention measure, has not been successful in decreasing prevalence of infection. There is therefore an urgent need to revise the current approach for the successful control of the disease. Clearly, these need to be integrated control measures.

Aflatoxin Exposure May Contribute to Chronic Hepatomegaly in Kenyan School Children

Background: Presentation with a firm type of chronic hepatomegaly of multifactorial etiology is common among school-age children in sub-Saharan Africa. Objective: Aflatoxin is a liver toxin and carcinogen contaminating staple maize food. In this study we examined its role in chronic hepatomegaly. Methods: Plasma samples collected in 2002 and again in 2004 from 218 children attending two schools in neighboring villages were assayed for aflatoxin exposure using the aflatoxin-albumin adduct (AF-alb) biomarker. Data were previously examined for associations among hepatomegaly, malaria, and schistosomiasis. Results: AF-alb levels were high in children from both schools, but the geometric mean (95% confidence interval) in year 2002 was significantly higher in Matangini [206.5 (175.5, 243.0) pg/mg albumin] than in Yumbuni [73.2 (61.6, 87.0) pg/mg; p < 0.001]. AF-alb levels also were higher in children with firm hepatomegaly [176.6 (129.6, 240.7) pg/mg] than in normal children [79.9 (49.6, 128.7) pg/mg; p = 0.029]. After adjusting for Schistosoma mansoni and Plasmodium infection, we estimated a significant 43% increase in the prevalence of hepatomegaly/hepatosplenomegaly for every natural-log-unit increase in AF-alb. In 2004, AF-alb levels were markedly higher than in 2002 [539.7 (463.3, 628.7) vs. 114.5 (99.7, 131.4) pg/mg; p < 0.001] but with no significant difference between the villages or between hepatomegaly and normal groups [539.7 (436.7, 666.9) vs. 512.6 (297.3, 883.8) pg/mg], possibly because acute exposures during an aflatoxicosis outbreak in 2004 may have masked any potential underlying relationship. Conclusions: Exposure to aflatoxin was associated with childhood chronic hepatomegaly in 2002. These preliminary data suggest an additional health risk that may be related to aflatoxin exposure in children, a hypothesis that merits further testing.

The Schistosoma mansoni tegumental-allergen-like (TAL) protein family: influence of developmental expression on human IgE responses

Background A human IgE response to Sm22.6 (a dominant IgE target in Schistosoma mansoni) is associated with the development of partial immunity. Located inside the tegument, the molecule belongs to a family of proteins from parasitic platyhelminths, the Tegument-Allergen-Like proteins (TALs). In addition to containing dynein-light-chain domains, these TALs also contain EF-hand domains similar to those found in numerous EF-hand allergens. Methodology/Principal Findings S. mansoni genome searches revealed 13 members (SmTAL1-13) within the species. Recent microarray data demonstrated they have a wide range of life-cycle transcriptional profiles. We expressed SmTAL1 (Sm22.6), SmTAL2, 3, 4, 5 and 13 as recombinant proteins and measured IgE and IgG4 in 200 infected males (7–60 years) from a schistosomiasis endemic region in Uganda. For SmTAL1 and 3 (transcribed in schistosomula through adult-worms and adult-worms, respectively) and SmTAL5 (transcribed in cercariae through adult-worms), detectable IgE responses were rare in 7–9 year olds, but increased with age. At all ages, IgE to SmTAL2 (expressed constitutively), was rare while anti-SmTAL2 IgG4 was common. Levels of IgE and IgG4 to SmTAL4 and 13 (transcribed predominantly in the cercariae/skin stage) were all low. Conclusions We have not measured SmTAL protein abundance or exposure in live parasites, but the antibody data suggests to us that, in endemic areas, there is priming and boosting of IgE to adult-worm SmTALs by occasional death of long-lived worms, desensitization to egg SmTALs through continuous exposure to dying eggs and low immunogenicity of larval SmTALs due to immunosuppression in the skin by the parasite. Of these, it is the gradual increase in IgE to the worm antigens that parallels age-dependent immunity seen in endemic areas.

Age-adjusted Plasmodium falciparum antibody levels in school-aged children are a stable marker of microgeographical variations in exposure to Plasmodium infection

BackgroundAmongst school-aged children living in malaria endemic areas, chronic morbidity and exacerbation of morbidity associated with other infections are often not coincident with the presence or levels of Plasmodium parasitaemia, but may result from long-term exposure to the parasite. Studies of hepatosplenomegaly associated with Schistosoma mansoni infection and exposure to Plasmodium infection indicate that differences that occur over 1–2 km in levels of Plasmodium transmission are related to the degree of exacerbation of hepatosplenomegaly and that Plasmodium falciparum schizont antigen (Pfs)-IgG3 levels may be a marker for the differing levels of exposure.MethodsTo investigate the validity of Pfs-IgG3 measurements as a tool to assess these comparative exposure levels on a microgeographical scale, cross-sectional community surveys were conducted over a 10 × 6 km study site in Makueni District, Kenya, during low and high malaria transmission seasons. During both high and low malaria transmission seasons, thick blood smears were examined microscopically and circulating Pfs-IgG3 levels measured from dried blood spot elute. GIS techniques were used to map prevalence of parasitaemia and Pfs-IgG3 levels.ResultsMicrogeographical variations in prevalence of parasitaemia were observed during the high but not the low transmission season. Pfs-IgG3 levels were stable between high and low transmission seasons, but increased with age throughout childhood before reaching a plateau in adults. Adjusting Pfs-IgG3 levels of school-aged children for age prior to mapping resulted in spatial patterns that reflected the microgeographical variations observed for high season prevalence of parasitaemia, however, Pfs-IgG3 levels of adults did not. The distances over which age-adjusted Pfs-IgG3 of school-aged children fluctuated were comparable with those distances over which chronic morbidity has previous been shown to vary.ConclusionAge-adjusted Pfs-IgG3 levels of school-aged children are stable and when mapped can provide a tool sensitive enough to detect microgeographical variations in malaria exposure, that would be useful for studying the aetiology of morbidities associated with long-term exposure and co-infections.

Hepatosplenomegaly in Kenyan schoolchildren: exacerbation by concurrent chronic exposure to malaria and Schistosoma mansoni infection

Objectives  Chronic exposure to malaria exacerbates Schistosoma mansoni‐associated hepatosplenomegaly in school‐aged children. However, residual hepatosplenomegaly after treatment of S. mansoni with concurrent mollusciciding suggests malaria could be an underlying cause of hepatosplenomegaly. We investigated the role of chronic malaria in childhood hepatosplenomegaly in the presence and absence of concurrent S. mansoni infection.

Chronic hepatosplenomegaly in African school children: a common but neglected morbidity associated with schistosomiasis and malaria.

Chronic hepatosplenomegaly, which is known to have a complex aetiology, is common amongst children who reside in rural areas of sub-Saharan Africa. Two of the more common infectious agents of hepatosplenomegaly amongst these children are malarial infections and schistosomiasis. The historical view of hepatosplenomegaly associated with schistosomiasis is that it is caused by gross periportal fibrosis and resulting portal hypertension. The introduction of ultrasound examinations into epidemiology studies, used in tandem with clinical examination, showed a dissociation within endemic communities between presentation with hepatosplenomegaly and ultrasound periportal fibrosis, while immuno-epidemiological studies indicate that rather than the pro-fibrotic Th2 response that is associated with periportal fibrosis, childhood hepatosplenomegaly without ultrasound-detectable fibrosis is associated with a pro-inflammatory response. Correlative analysis has shown that the pro-inflammatory response is also associated with chronic exposure to malarial infections and there is evidence of exacerbation of hepatosplenomegaly when co-exposure to malaria and schistosomiasis occurs. The common presentation with childhood hepatosplenomegaly in rural communities means that it is an important example of a multi-factorial disease and its association with severe and subtle morbidities underlies the need for well-designed public health strategies for tackling common infectious diseases in tandem rather than in isolation.

Hepatosplenomegaly Is Associated with Low Regulatory and Th2 Responses to Schistosome Antigens in Childhood Schistosomiasis and Malaria Coinfection

ABSTRACT Hepatosplenomegaly among Kenyan schoolchildren has been shown to be exacerbated where there is transmission of both Schistosoma mansoni and Plasmodium falciparum. This highly prevalent and chronic morbidity often occurs in the absence of ultrasound-detectable periportal fibrosis and may be due to immunological inflammation. For a cohort of school-age children, whole-blood cultures were stimulated with S. mansoni soluble egg antigen (SEA) or soluble worm antigen (SWA). Responses to SWA were found to be predominantly Th2 cytokines; however, they were not significantly associated with either hepatosplenomegaly or infection with S. mansoni or P. falciparum. In comparison, SEA-specific Th2 cytokine responses were low, and the levels were negatively correlated with S. mansoni infection intensities and were lower among children who were coinfected with P. falciparum. Tumor necrosis factor alpha levels in response to stimulation with SEA were high, and a negative association between presentation with hepatomegaly and the levels of the regulatory cytokines interleukin-6 and transforming growth factor β1 suggests that a possible mechanism for childhood hepatomegaly in areas where both malaria and schistosomiasis are endemic is poor regulation of an inflammatory response to schistosome eggs.

Hepatosplenomegaly associated with chronic malaria exposure: evidence for a pro-inflammatory mechanism exacerbated by schistosomiasis

In sub‐Saharan Africa, chronic hepatosplenomegaly, with palpable firm/hard organ consistency, is common, particularly among school‐aged children. This morbidity can be caused by long‐term exposure to malaria, or by Schistosoma mansoni, and it is exacerbated when these two occur together. Although immunological mechanisms probably underlie the pathogenic process, these mechanisms have not been identified, nor is it known whether the two parasites augment the same mechanisms or induce unrelated processes that nonetheless have additive or synergistic effects. Kenyan primary schoolchildren, living in a malaria/schistosomiasis co‐transmission area, participated in cross‐sectional parasitological and clinical studies in which circulating immune modulator levels were also measured. Plasma IL‐12p70, sTNF‐RII, IL‐10 and IL‐13 levels correlated with relative exposure to malaria, and with hepatosplenomegaly. Soluble‐TNF‐RII and IL‐10 were higher in children infected with S. mansoni. Hepatosplenomegaly caused by chronic exposure to malaria was clearly associated with increased circulating levels of pro‐inflammatory mediators, with higher levels of regulatory modulators, and with tissue repair cytokines, perhaps being required to control the inflammatory response. The higher levels of regulatory modulators amongst S. mansoni infected children, compared to those without detectable S. mansoni and malarial infections, but exposed to malaria, suggest that S. mansoni infection may augment the underlying inflammatory reaction.

Identification of a Novel Antigen of Schistosoma mansoni Shared with Plasmodium falciparum and Evaluation of Different Cross-Reactive Antibody Subclasses Induced by Human Schistosomiasis and Malaria

ABSTRACT Plasmodium falciparum and Schistosoma mansoni are often found in human coinfections, and cross-reactive antibodies to different components of the two parasites have been detected. In this work, we identified a cross-reactive S. mansoni gene product, referred to as SmLRR, that seems to belong to the leucine-rich repeat protein family. Comparative analysis of SmLRR revealed 57% similarity with a putative gene product encoded in the P. falciparum genome. Antibodies to SmLRR were found in experimental infections and in both S. mansoni- and P. falciparum-infected individuals. Correlative analysis of human anti-SmLRR responses in Kenya and Uganda suggested that malaria and schistosomiasis drive the immunoglobulin G3 (IgG3) and IgG4 isotypes, respectively, against SmLRR, suggesting that there is differential regulation of cross-reactive isotypes depending on the infection. In addition, the levels of anti-SmLRR IgG4, but not the levels of IgG3, correlated positively with the intensity of S. mansoni infection.

Incomplete glycosylation and defective intracellular targeting of mutant solute carrier family 11 member 1 (Slc11a1)

Solute carrier family 11 member 1 (Slc11a1, formerly Nramp1) is a highly glycosylated, 12 transmembrane domain protein expressed in macrophages. It resides in the membrane of late endosomes and lysosomes, where it functions as a bivalent cation transporter. Mice susceptible to infection by various intracellular pathogens including Leishmania donovani and Salmonella typhimurium carry a glycine to aspartic acid substitution at position 169 (G169D, Gly(169)-->Asp), within transmembrane domain 4 of Slc11a1. To investigate the molecular pathogenesis of infectious disease susceptibility, we compared the behaviour of heterologously and endogenously expressed wild-type and mutant Slc11a1 by immunofluorescence, immunoelectron microscopy and Western-blot analysis. We found occasional late endosome/lysosome staining of mutant protein using immunoelectron microscopy, but most of the mutant Slc11a1 was retained within the ER (endoplasmic reticulum). Using glycosylation as a marker for protein maturation in two independent heterologous expression systems, we found that most mutant Slc11a1 existed as an ER-dependent, partially glycosylated intermediate species. Correct endosomal targeting of wild-type Slc11a1 continued despite disruption of N-glycosylation sites, indicating that glycosylation did not influence folding or sorting. We propose that the G169D mutation causes localized misfolding of Slc11a1, resulting in its retention in the ER and manifestation of the loss of function phenotype.