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It is widely held that hookworm infections have an immunomodulatory impact on the host, but whether the converse is true remains unclear. Immunity against adult-stage hookworms is largely mediated by Type 2 immune responses driven by the transcription factor Signal Transducer and Activator of Transcription 6 (STAT6). This study investigated whether serial passage of the rodent hookworm <jats:italic>Nippostrongylus brasiliensis<\/jats:italic> in STAT6-deficient mice (STAT6 KO) caused changes in parasites over time. After adaptation to STAT6 KO hosts, <jats:italic>N<\/jats:italic>. <jats:italic>brasiliensis<\/jats:italic> increased their reproductive output, feeding capacity, energy content, and body size. Using an improved <jats:italic>N<\/jats:italic>. <jats:italic>brasiliensis<\/jats:italic> genome, we found that these physiological changes corresponded with a dramatic shift in the transcriptional landscape, including increased expression of gene pathways associated with egg production, but a decrease in genes encoding neuropeptides, proteases, SCP\/TAPS proteins, and transthyretin-like proteins; the latter three categories have been repeatedly observed in hookworm excreted\/secreted proteins (ESPs) implicated in immunosuppression. Although transcriptional changes started to appear in the first generation of passage in STAT6 KO hosts for both immature and mature adult stages, downregulation of the genes putatively involved in immunosuppression was only observed after multiple generations in this immunodeficient environment. When STAT6 KO-adapted <jats:italic>N<\/jats:italic>. <jats:italic>brasiliensis<\/jats:italic> were reintroduced to a naive WT host after up to 26 generations, this progressive change in host-adaptation corresponded to increased production of inflammatory cytokines by the WT host. Surprisingly, however, this single exposure of STAT6 KO-adapted <jats:italic>N<\/jats:italic>. <jats:italic>brasiliensis<\/jats:italic> to WT hosts resulted in worms that were morphologically and transcriptionally indistinguishable from WT-adapted parasites. This work uncovers remarkable plasticity in the ability of hookworms to adapt to their hosts, which may present a general feature of parasitic nematodes.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011797","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T18:34:14Z","timestamp":1702319654000},"page":"e1011797","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hookworms dynamically respond to loss of Type 2 immune pressure"],"prefix":"10.1371","volume":"19","author":[{"given":"Annabel A.","family":"Ferguson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M.","family":"Inclan-Rico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dihong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah D.","family":"Bobardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LiYin","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Gouil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E.","family":"Ritchie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron R.","family":"Jex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erich M.","family":"Schwarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meera G.","family":"Nair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adler R.","family":"Dillman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2449-5365","authenticated-orcid":true,"given":"De\u2019Broski R.","family":"Herbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,11]]},"reference":[{"key":"ppat.1011797.ref001","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198832140.001.0001","volume-title":"Evolutionary Parasitology: The Integrated Study of Infections, Immunology, Ecology, and Genetics [Internet].","author":"P. 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