The aim of this thesis was to get a detailed insight into the epidemiological patterns of Schistosoma infection and associated morbidity on a micro-geographical scale in Schistosoma mansoni and S. haematobium co-endemic areas. A S. mansoni and S. haematobium co-endemic focus in the north of Senegal was selected as the primary study site. The small scale of this study allowed a detailed, multidisciplinary analysis of complex infection and morbidity patterns. Moreover, it enabled us to take the well-known focality of schistosomiasis into account (Chapter 1). We observed prevalences of 61% and 50% for S. mansoni and S. haematobium infection, respectively. Most of these infections were mixed S. mansoni and S. haematobium infections (53%). In comparison to single infections, mixed infections were of higher intensity. Eight percent of the infected people also showed ectopic excretion of Schistosoma eggs (mainly S. mansoni in urine; Chapter 2). While elevated S. haematobium infection intensities predisposed for S. haematobium-specific urinary tract morbidity, the presence of S. mansoni in co-infections tended to protect against this. The latter effect was most pronounced in people with ectopic S. mansoni egg excretion. On the other hand, no association was found between S. mansoni-specific hepatic fibrosis and Schistosoma infection. This is likely due to a slower disease onset in S. mansoni as compared to S. haematobium infection. Indeed, the delay between the age peak for S. mansoni infection and morbidity was >10 years, while such a delay could not be observed for S. haematobium (Chapter 3). We were the first to look into the micro-geographical distribution of chronic Schistosoma morbidity. In contrast to classical epidemiological analyses (see Chapter 3), spatial analysis did reveal a clear association between S. mansoni infection and morbidity. It was shown that adults living adjacent to the main Schistosoma transmission site were more than six times more likely to develop severe S. mansoni-specific hepatic fibrosis than their counterparts living farther away. Children living in the same spot were also more at risk of heavy S. mansoni infection, indicating that cumulative exposure to Schistosoma eggs is likely to be the main driver of chronic morbidity in schistosomiasis (Chapter 4). We explored immune responses in the two Schistosoma infections in this population by means of whole blood cytokine responses. Cytokine responses to adult worm antigens were used as a proxy for host responses to living adult worms, and thus infection. Cytokine responses to soluble Schistosoma egg antigens were used as a proxy for the egg-induced responses that may have contributed to the observed morbidity patterns. It was found that S. haematobium antigens induce higher cytokine levels than those of S. mansoni. This supports the idea that the first species may be more immunogenic. This hypothesis corresponds with our epidemiological findings: 1) in line with previous studies, we found the S. haematobium age curve to decline more steeply after adolescence than that of S. mansoni; and 2) we observed more S. haematobium- than S. mansoni-specific morbidity (83% versus 27%). Our investigations did not reveal any interspecies differences in the immunological phenotypes that were induced. Both Schistosoma species were associated with a modified Th2 response in a dose-dependent manner. Such a response is characteristic for Schistosoma infection (Chapter 5). Subsequently, the innate immune responses that generally precede and shape these adaptive cytokine responses were investigated. This study was performed in children from a S. haematobium mono-endemic area in Lambaréné, Gabon. While children infected with S. haematobium produced more of the anti-inflammatory cytokine IL-10 than uninfected children in response to adaptive stimuli (egg and worm antigens), their innate immune response to TLR ligands was more pro-inflammatory (TNF-α) than that of uninfected children. Hence, schistosomal infection suppresses the host’s adaptive immune system but does not appear to affect innate stimulation with single TLR ligands. This indicates that schistosomiasis does not induce a general suppression of the host immune system (Chapter 6). This thesis provides a novel, holistic approach to understanding schistosomiasis. It has led to important new insights into demographic and geographic patterns of S. mansoni and S. haematobium on a micro scale, and provides new leads for further research on disease etiology and underlying mechanisms. Further studies are necessary to investigate to which extent these results can be extrapolated over time and to other populations. Such knowledge is key to rationalizing and optimizing current schistosomiasis control strategies, particularly in co-endemic areas. An improved understanding of this complex disease would furthermore greatly aid in developing successful elimination strategies in the future (Chapter 7).
|Place of Publication
|Published - 2014