This TMRC presents an innovative approach to understand host-parasite dynamics of Schistosoma mansoni infection in an endemic population in Brazil. The overall goal of this TMRC is to utilize new information on resistance-related host immune response, combined with fine-scale data on environmental exposures, in order to develop an informative, detailed model of transmission in endemic areas that can be used to efficiently allocate monitoring and preventive control efforts for schistosomiasis. The research will provide detailed study of immune responses among individuals who develop resistance to reinfection after treatment - termed here. Drug Induced Resistance (DIR). For the first time, by evaluating immune responses using a novel broad-based immunomics approach, we will be able to identify the constellation of parasite proteins recognized by DIR individuals. Such analysis will identify important biomarkers of resistance that can be used to time the onset of resistance to infection according to the dynamics of individual re-exposure. Besides the impact on the immune response, intensive treatment also has significant effect on the parasite population. We will apply molecular tools that will complement traditional epidemiology to provide a better understanding of disease transmission, the impact of praziquantel drug treatment over time and the adaptability of the schistosome parasite. We will use new molecular and statistical tools to assess the adaptive potential and identify focal points of transmission of the S. mansoni. The role of eco-social and environmental factors will be evaluated using an agent-based mathematical model. Within-host models of schistosomiasis infection that would account for the effects of environment, exposure to the infection, possible effect of drug treatment and other (helminth) coinfections will also be developed in the context of this integrated approach. Taken together, the immunomics, understanding of the parasite population diversity and the eco-socio-economic, behavioral, and spatial components of exposure, this project will ultimately provide an advanced model of transmission that can be used for development of optimized control programs for schistosomiasis in Brazil and other endemic areas.
The results will provide key data that are needed to model schistosome transmission and drug selection and result in the design of more effective control interventions. Project 1: An Immunomics Approach to Explore Drug-Induced Resistance to Schistosomes Project Leader: Rodrigo Correa-Oliveira, PhD (Description as provided by applicant): Schistosoma mansoni infection usually peaks in early adolescence and declines in adulthood, a pattern that has led to the hypothesis that individuals in endemic areas can acquire an age-related resistance to reinfection. The acquisition of this immunity is coincident with the natural death of worms, when they release previously inaccessible surface and subsurface schistosome antigens to the immune system. As the antibody response expands with ongoing worm death, a protective immune response evolves overtime. However, an accelerated version of acquired immunity can be induced """"""""when individuals experience repeated rounds of treatment with the drug praziquantel (PZQ). We hypothesize that both natural (age-related) and Drug-Induced Resistance (DIR) to S. mansoni reinfection have the following characteristics: (1) antibodies are generated to a repertoire of antigens released by PZQ or worm death and not to a single or a few key antigen(s) and (2) there is a gradual expansion of the antibody repertoire as it evolves with worm death either naturally or by PZQ treatment until resistance is achieved. In TMRC Project 1, we utilize a systems biology approach (immunomics) to explore the evolution of DIR in a cohort of children resident in an area of high S. mansoni transmission. Recent advances in high-order multiplexing technologies, such as proteome microarrays, enable us to determine the immunomic profile of an individual to an annotated predicted proteome of S. mansoni that contains 1000 proteins. This S. mansoni protein microarray will be used to determine the difference in immunomic profiles of individuals who develop DIR to S. mansoni and age, sex, and exposure-matched individuals who are chronically re-infected with S. mansoni. The kinetics of immunomic profiles of DIR individuals will also be determined. Finally, we plan to combine the individual immunomic profiles with data from Projects 2 and 3 of the TMRC using a """"""""parasite-immune"""""""" agent mathematical model for putative drug-effect on resistance (DIR). A key aspect of our strategy is the capacity to identify large populations of antigens recognized by the antibody responses of a well-characterized cohort who display drug-induced resistance to schistosomiasis (DIRs).
The outcome of this study will be an """"""""antibody repertoire"""""""" associated with the sequential acquisition of DIR. This approach could prove to be a useful strategy for identifying the drug regimens that most efficiently induce immunity as well as provide insight into the kinetics of DIR in areas of S. mansoni transmission. This approach will also shed light on the selection of antigens for vaccine development.
|Chevalier, Frédéric D; Le Clec'h, Winka; Eng, Nina et al. (2016) Independent origins of loss-of-function mutations conferring oxamniquine resistance in a Brazilian schistosome population. Int J Parasitol 46:417-24|
|Chevalier, Frédéric D; Le Clec'h, Winka; Alves de Mattos, Ana Carolina et al. (2016) Real-time PCR for sexing Schistosoma mansoni cercariae. Mol Biochem Parasitol 205:35-8|
|de Assis, Rafael Ramiro; Ludolf, Fernanda; Nakajima, Rie et al. (2016) A next-generation proteome array for Schistosoma mansoni. Int J Parasitol 46:411-5|
|Gazzinelli, Maria Flávia; Lobato, Lucas; Andrade, Gisele et al. (2016) Improving the understanding of schistosomiasis among adolescents in endemic areas in Brazil: A comparison of educational methods. Patient Educ Couns 99:1657-62|
|Bonin, Camila P; Baccarin, Raquel Y A; Nostell, Katarina et al. (2013) Lipopolysaccharide-induced inhibition of transcription of tlr4 in vitro is reversed by dexamethasone and correlates with presence of conserved NF?B binding sites. Biochem Biophys Res Commun 432:256-61|