Immune targets for schistosomiasis control identified by a genome-wide association study of East African snail vectors

Abstract

Schistosomiasis, afflicting >260 million people worldwide, could be controlled by preventing infection of freshwater snail vectors. Intestinal schistosomiasis, caused by Schistosoma mansoni, occurs predominantly in Sub-Saharan Africa and is vectored by Biomphalaria sudanica and related Biomphalaria species. Despite their importance in transmission, very little genomic work has been initiated in African snails, thus hindering development of novel control strategies. To identify genetic factors influencing snail resistance to schistosomes, we performed a pooled genome-wide association study (pooled-GWAS) on the offspring of B. sudanica collected from a persistent hotspot of schistosomiasis in Lake Victoria, Kenya, and exposed to sympatric S. mansoni. Results of the pooled-GWAS were used to develop an amplicon panel to validate candidate loci by genotyping individual snails. This validation revealed two previously uncharacterized, evolutionarily dynamic regions, SudRes1 and SudRes2, that were significantly associated with resistance. SudRes1 includes receptor-like protein tyrosine phosphatases and SudRes2 includes a class of leucine-rich repeat-containing G-protein coupled receptors, both comprising diverse extracellular binding domains, suggesting roles in pathogen recognition. No loci previously tied to schistosome resistance in other snail species showed any association with compatibility suggesting that loci involved in the resistance of African vectors differ from those of neotropical vectors. Beyond these two loci, snail ancestry was strongly correlated with schistosome compatibility, indicating the importance of population structure on transmission dynamics and infection risk. These results provide the first detail of the innate immune system of the major schistosome vector, B. sudanica, informing future studies aimed at predicting and manipulating vector competence. Significance StatementAlthough schistosomiasis-associated morbidity and mortality have reduced significantly due to chemotherapy, interruption of transmission, a WHO goal, requires complimentary novel snail vector-focused interventions. We performed a genome-wide association study of snails exposed to schistosomes in an endemic area of high transmission in Kenya. We identified two snail genomic regions that were associated with snail immunity to schistosomes, and which had not previously been tied to parasite infection. The characterized protein structures are plausibly consistent with a role in host-parasite interaction. Therefore, they are new, potential targets for schistosomiasis control. These results show the need for focused research on transmission-relevant vectors and their genetic variants that could have a large impact on schistosome transmission dynamics and human health risk.