Thursday, April 3, 2025
4/3/2025
Reciprocal genetics of recently-evolved vertebrate immunity and helminth counter-adaptation - PROJECT SUMMARY/ABSTRACT Vertebrates evolved sophisticated immune systems to eliminate infections by helminth parasites (tapeworms, nematodes). Nevertheless, helminths often succeed in establishing persistent infections because they evolved strategies to evade or manipulate their host’s immune system. Because of this host- parasite co-evolution, infection success is expected to depend on an epistatic interaction between host immune genes and parasites’ immune-evasion genes. But, the immunogenetic mechanisms underlying this between-species epistasis remains poorly understood, because most studies focus on immunological effects of either host genes, or parasite genes, studied separately. Few experimental models of infection are amenable to ‘reciprocal mapping’ – the concurrent genetic analysis of both interacting species. A small fish, the threespine stickleback (Gasterosteus aculeatus), and its parasitic tapeworm (Schistocephalus solidus), offer an experimentally tractable system for reciprocal genetic analysis of trans- species epistasis between a vertebrate host and cestode parasite. Some natural populations of stickleback evolved an aggressive inflammatory response to tapeworm infection that limits tapeworm growth and survival, but results in severe and persistent fibrosis throughout the body cavity, a new model for human Encapsulating Peritoneal Sclerosis. Although an effective defense against infection, this fibrosis is also pathological, limiting fish mobility and reproduction. To ameliorate this pathology, some stickleback populations evolved a remarkable capacity to recover, partially reversing earlier fibrosis. Other populations evolved a tolerance strategy, allowing tapeworm growth by suppressing fibrosis at the start of infection; but these genotypes are unable to reverse fibrosis when it does occur. Aim 1 is to identify the genetic basis of naturally-evolved variation among stickleback populations in the speed of fibrosis onset, maximum severity, and reversal. We will achieve this using a triangulation approach merging QTL linkage mapping, population genomics, and experimental evolution. CRISPR/cas9 editing will be used to confirm the phenotypic effect of mapped genes. However, fibrosis is also a phenotypic outcome of heritable differences between parasite populations. So, Aim 2 is to identify tapeworm genes that modulate the host fibrosis response, using QTL mapping, population genomics and experimental gene editing. Aim 3 merges the results of Aims 1&2, to test for between-species epistatic interactions (synergy between host and parasite genes) regulating onset, severity, and reversal of fibrosis. Ultimately, our goal is to identify host and parasite genes that jointly determine infection success, and influence fibrosis severity or suppression, to understand (i) mechanisms of immunity to peritoneal helminth infections, (ii) how the cestode evolved to suppress or evade host immunity, and (iii) the genes underlying variation in onset, severity, and recovery from fibrosis that is both immunologically adaptive but also pathological.
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