Schistosomiasis is by far the most important helminth parasitic disease of humans. Vaccines are unavailable, the only effective treatment involves repeated dosing with a single drug (praziquantel), and now drug resistance is a major concern. Schistosomes require aquatic snails for transmission. Understanding the molecular mechanisms by which snails and schistosomes interact is key for new strategies to interrupt transmission. Decades of painstaking research on the molecular basis of snail-schistosome compatibility have yielded just a handful of candidate genes or mechanisms. Using a genome-wide association mapping approach, we recently identified a small region of the genome of the snail, Biomphalaria glabrata, in which allelic variation at an unknown gene has a very strong effect on resistance to Schistosoma mansoni. This region contains 10 putative coding genes, none of which was previously known to be immune relevant in molluscs. The goal of this proposal is to unambiguously identify which of the genes in this region is causal. Firstly, candidate genes will be ranked by their likelihood of being the causal gene. Ranking will be based on whether or not alleles on the resistant versus susceptible haplotypes (versions of the region) differ in (a) expression levels or (b) amino acid sequence, together with information on putative gene function. Then, for each remaining candidate in ranked order, we will functionally test whether allelic variation at that locus actually controls resistance. This will be accomplished using RNA interference (RNAi) and allele-specific RNAi (i.e. knock down one allele or the other in heterozygotes). These complementary approaches allow one to evaluate causality for alleles that differ in either expression level or amino acid sequence. Innovation: Association mapping through functional identification of a causal gene illustrates a fresh new approach in the field of Biomphalaria genetics. The use of inbred lines with RNAseq (whole-genome expression) data, RNAi and allele-specific RNAi in a hypothesis testing framework is also novel. Significance: Identifying new resistance pathways will indicate new ways to potentially interfere with parasite transmission (i.e. how do some snails block schistosomes' ability to detect, penetrate or successfully develop within a host?). Identifying resistance genes in snails is also essential for evaluating whether genetic manipulation of snail populations might become a viable approach for blocking transmission. Understanding resistance in snails should also aid the search for genes in the parasite that control host specificity. Finally, molluscs are intermediate hosts for many diseases of medical and economic importance worldwide. None of the genes in the region of association have been previously identified as immune-relevant in molluscs. Thus, whichever gene turns out to be causal, it will identify a new mechanism of disease resistance in this important group of disease-transmitting organisms.

Public Health Relevance

Schistosomes are water-borne blood-flukes that are transmitted by snails, infecting over 200 million people in more than 70 countries, and causing severe and chronic disability. We will identify new genes that make some snails naturally resistant to infection by schistosomes. Identifying such genes will reveal potential new targets to interfere with parasite transmission at the snail stage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI109134-03
Application #
9130478
Study Section
Vector Biology Study Section (VB)
Program Officer
Joy, Deirdre A
Project Start
2014-08-01
Project End
2017-07-31
Budget Start
2015-08-02
Budget End
2016-07-31
Support Year
3
Fiscal Year
2015
Total Cost
$363,188
Indirect Cost
$113,188
Name
Oregon State University
Department
Type
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97331
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Allan, Euan R O; Tennessen, Jacob A; Sharpton, Thomas J et al. (2018) Allelic Variation in a Single Genomic Region Alters the Microbiome of the Snail Biomphalaria glabrata. J Hered 109:604-609
Allan, Euan R O; Blouin, Michael S (2018) Allelic variation partially regulates galactose-dependent hydrogen peroxide release from circulating hemocytes of the snail Biomphalaria glabrata. Fish Shellfish Immunol 72:111-116
Allan, Euan R O; Tennessen, Jacob A; Bollmann, Stephanie R et al. (2017) Schistosome infectivity in the snail, Biomphalaria glabrata, is partially dependent on the expression of Grctm6, a Guadeloupe Resistance Complex protein. PLoS Negl Trop Dis 11:e0005362
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Tennessen, Jacob A; Théron, André; Marine, Melanie et al. (2015) Hyperdiverse gene cluster in snail host conveys resistance to human schistosome parasites. PLoS Genet 11:e1005067