Hookworms dynamically respond to loss of Type 2 immune pressure

The impact of the host immune environment on parasite transcription and fitness is currently unknown. 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 Nippostrongylus brasiliensis in STAT6-deficient mice (STAT6 KO) caused changes in parasites over time. After adaptation to STAT6 KO hosts, N. brasiliensis increased their reproductive output, feeding capacity, energy content, and body size. Using an improved N. brasiliensis 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 N. brasiliensis 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 N. brasiliensis 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. Hookworms infect 170-440 million people globally. Our goal in this study was to understand how the host immune environment affects hookworm fitness and gene expression. It is well accepted that protective immunity against hookworms depends on mechanisms controlled by the Signal Transducer and Activator of Transcription 6 (STAT6). Therefore, we used mice lacking STAT6 (STAT6 KO) to serve as a permissive environment for survival of the rodent hookworm Nippostrongylus brasiliensis. One passage into STAT6 KO hosts resulted in immediate transcriptional changes, including increased feeding and egg production pathways, corresponding with measured increases in fecundity, survival, body size, and feeding observed after additional passages. It took multiple generations (up to 26) of STAT6 KO hosts to see the reduced transcription of genes thought to mediate evasion of the host immune system. Despite WT hosts having an enhanced immune response to STAT6 KO-adapted N. brasiliensis, this line of worms survived as well as the WT-adapted N. brasiliensis and quickly lost the changes they had acquired during passage through STAT6 KO hosts. Our findings suggest that hookworms dynamically alter their transcriptional profile to suit their immediate host immune environment.