Contribution of PU.1 and STAT6 to fibrosis-mediated growth suppression of the Diphyllobothriidae family cestode, Schistocephalus solidus.

Abstract

Abstract Threespine stickleback (Gasterosteus aculeatus) fish are naturally infected with the Diphyllobothriidae family tapeworm, Schistocephalus solidus. The anti-parasite response to this body cavity infection varies greatly among wild stickleback populations. Some populations generate extensive peritoneal fibrosis which suppresses cestode grown, thereby preventing the parasite from reaching sexual maturity and blocking its ability to infect its terminal host. In extreme cases this response can encapsulate the cestode. On the other hand, other fish populations tolerate S. solidus, carry heavy parasite burdens, grow parasites 34-fold larger than resistant fish, and do not produce fibrosis. Combined genetic mapping and population genomics identified regions of the genome associated with this resistance-tolerance axis. Quantitative trait loci (QTL) mapping of the fibrosis phenotype led us to a 78bp deletion in SPI1b which encodes the transcription factor PU.1 which is associated with the initiation of tissue fibrosis. This deletion was fixed in tolerant fish, but not resistant fish. SPI1b expression increases with infection and is higher in fibrotic fish compared to non-fibrotic controls. QTL mapping of cestode mass detected STAT6 on Ch 12, which is associated with alternatively activated macrophages and fibrosis. In tolerant fish, but not resistant, a deletion in stat6 exon 5 is nearly fixed. Several additional QTL were also found containing genes associated with fibrosis initiation or regulation, evidence for strong selection on this anti-parasite mechanism and identifying pathways involved in the regulation of a pathologic fibrotic response against a Diphyllobothriidae cestode.