HOOKWORMS DYNAMICALLY RESPOND TO LOSS OF TYPE 2 IMMUNITY

Hookworms are highly successful parasites, having coevolved with humans since we have been a species. This has culminated in a balance of hookworm traits that promote growth and fecundity with those that enable host tolerance of the infection. This project explores the coevolved traits from hookworms and the host immune response to worms. Type 2 immunity targets infections with parasitic worms, and is comprised of activities that directly harm or eject worms from their hosts. Many of these are dependent on the targets of the transcription factor Signal transduction and Activator of Transcription 6 (STAT6), which gets activated by signaling cytokines Interleukin (IL) -4 and -13. To counter this, worms possess a large repertoire of excreted and secreted (E/S) products that are released into the host environment and enable parasitism of the host, by both allowing tissue migration and by suppressing the host immune response. This work sought to test the central hypothesis that STAT6-dependent immune responses have selected hookworm traits that enable host tolerance of this infection. It did so by experimentally evolving hookworms in STAT6 KO hosts via serial passaging, and then analyzing worm traits as well as the host immune response to infection with adapted worms. The hookworms derived from STAT6 KO hosts were larger and more fecund, but had a contracted array of E/S proteins. This suggested that size and reproduction were enhanced over the expression of E/S when hosts lack an immune response. Surprisingly, this adaptation did not result in loss of hookworm traits that promoted growth, survival and reproduction when STAT6 immune responses were restored via the infection of WT mice with STAT6 KO-adapted worms. However, during this infection, the hosts displayed an increased inflammatory immune response in both the lungs and the gut, which likely led to increased mortality of the hosts. This work suggests that a persistent evolutionary pressure of STAT6 dependent immune responses is needed for maintaining immune-suppressing traits in hookworm populations.