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I. Project Description
A. State of the art
Schistosoma and microfilarial species, as well as intestinal helminths are helminth infections and Neglected Tropical Diseases (NTD) with an enormous impact on affected populations. They are highly prevalent in Africa where they share the same geographical distribution with Plasmodium falciparum and consequently affect the same population. Epidemiological and experimental evidence suggests that chronic helminthiasis can alter the host response to a concomitant Plasmodium infection. To quote a review from Nacher et al. malaria has been found in many reports to be “less noisy” in helminth-infected subjects who often have less fever and are less likely to develop severe malaria. The influence of helminth on malariometric indices is thought to reflect a profound effect of helminth infection on the host’s immune response to P. falciparum infection. Chronic helminth infection has been shown to be associated with an impairment of the protective immune response to Plasmodium. Protection against malaria is linked with a Th1-dominated response and with a predominant production of cytophilic antibodies (IgG1 and IgG3). However, the immune phenotype of helminth infected subjects is generally characterized by a Th2-skewed immune response and marked by the production of non-cytophilic antibodies (and IgE) as well as by a strong regulatory network that can dampen the Th1 type response needed to clear the Plasmodium infection. Therefore, in helminth infected subjects living in malaria endemic areas the natural consequence of such an altered immune response would be a higher susceptibility to Plasmodium spp. (but with reduced severity), an increase of the incidence of malaria and as a consequence an increase of its transmission intensity.
This latter effect of helminth on malaria transmission is of particular interest and has not yet been fully investigated despite a reported increase in P. falciparum gametocyte carriage in malaria and helminth coinfected subjects by comparison to those without helminths. On the other hand using a mice model, Noland et al. were able to show that helminth-infected mice were more attractive to mosquitoes than their uninfected relatives. In addition they reported that transmission of Plasmodium gametocytes to mosquitoes was higher in mosquitoes which fed on helminth infected mice. Taken together these data imply that helminths can significantly affect malaria transmission in area of co-endemicity. This is of particular interest since this effect can interfere with current effort to eliminate malaria in these areas. So far it is unknown how co-infection may affect transmission intensity and there are no published studies that have assessed this question under natural settings. On one hand helminth infections are usually associated with malnutrition and anaemia, which can increase Plasmodium spp. gamecytogenesis. On the other hand the host immune response to the sexual stages of Plasmodium spp. may be altered by a concurrent helminth infection. A combination of these and possibly other effects may support the hypothesis that helminths have an effect on malaria transmission. In the context of malaria elimination as well as resistance containment of drugs like artemisinins, reducing transmission is crucial. Hence, investigation of helminth coinfections on transmissibility of P. falciparum is highly relevant on the public health level.
B. Preliminary work
In Lambaréné and surroundings malaria is hyperendemic and transmitted perennially. P. falciparum is responsible for 90% of malaria cases. Asymptomatic P. falciparum infection, which contributes to sustaining the reservoir of infection, is frequent and occurs in approx. 52% of afebrile adults.
Soil-transmitted helminths, filaria parasites and Schistosoma haematobium are equally present and highly prevalent in Lambaréné and its surrounding. In a study conducted in 2010 in Gabon, where 512 children aged from 1 to 5 years were assessed we found that 30% had an intestinal helminth infection and 7% were infected with S. haematobium. Of note, this prevalence significantly increased with age with 62% and 43% of school-age children infected with intestinal helminths and S. haematobium, respectively (own unpublished data). As a consequence of the geographical overlap between helminths and Plasmodium spp. it is likely that these parasites co-infect the same human host. We found that the prevalence of helminths and P. falciparum coinfection was 6% in children aged from 1 to 5 years and up to 55% in school-age children (own unpublished data). Interestingly, we also observed that the prevalence of P. falciparum carriage was higher in subjects infected with S. haematobium when compared to S. haematobium uninfected control subjects (47% in infected vs 26% in S. haematobium uninfected subjects, p = 0.003). This association suggests a higher susceptibility of S. haematobium-infected subjects to asymptomatic malaria. Helminths may increase the susceptibility of endemically exposed subjects to plasmodia infection through the modulation of their immune system. In a series of studies to assess the effect of S. haematobium on the immune response of their human host, we found that schistosoma infected subjects produce more IL-10, had an increased or a decreased secretion of distinct cytokines and showed an alteration of their B cell immune response. Moreover, in an exploratory study that aimed to assess the effect of intestinal helminth on the immunogenicity of a malaria vaccine candidate, we found that Trichuris trichiura infected children had a reduced antibody response to the vaccine antigens when compared to their uninfected counterpart.
More recently, in the framework of malaria and helminth control studies, we started to explore the effect of helminths on malaria transmission. One possibility is that an increase of the proportion of asymptomatic P. falciparum carriers (see above) expands the human reservoir of the parasite and therefore the likelihood of transmission to mosquitoes. In addition to an expansion of the human reservoir, we observed that subjects chronically infected with S. haematobium have more gametocytes and significantly lower IgG level against Pfs48/45 (mean of the Pfs48/45 antibody level: 44.2 in S. haematobium infected subjects vs 53.2 in uninfected subjects, p= 0.037). Pfs48/45 is a major gametocyte antigen capable of blocking gamete fertilization in the mosquito gut and consequently blocking further transmission. So far, no functional analyses have been done and intriguingly we observed that the level of IgG against Pfs230, another gametocyte antigen, was similar between the groups of this pilot study. In contrast to Schistosoma infections we did not observe a significant effect of microfilaria neither on gametocyte carriage nor on the humoral response to gametocyte antigens.
To date this small exploratory study is the first to assess the effect of helminths on gametocyte carriage and immune responses to gametocyte antigens. It shows that helminths are associated with a higher gametocytemia that may be due to impaired immune response to gametocytes. If and how this effect affects malaria transmission and how reduction in helminth burden affects transmission is not known. We believe that the results of our pilot study warrant investigation in a larger study that is specifically designed to address the question of transmission under strong infection pressure with helminths.
C. Relevance of the study for fields other than science
The results generated by this study will be relevant for policy maker working in the field of helminthiasis and/or malaria. Indeed this project fits within the WHO top ten priority research areas for helminth infections in the way that:
– It will increase our understanding of how helminths modulate host parasite interactions and,
– It will give more insight on the impact of helminths on the epidemiological feature and immune response to other pathogens.
On the other hand the proposed project will broaden our current knowledge on factors that can influence malaria transmission, which is one of the top research priorities for malaria control. Besides immediate scientific and public health implications, such a study enables the participating African centres to perform further studies on transmission of malaria, including functional, immunological and entomological approaches. In the light of current control and malaria elimination efforts, this is a key competence and likely to provide significant knowledge in the coming years.
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