BackgroundDynamic interactions between the host and gastrointestinal microbiota play an important role for local and systemic immune homeostasis. Helminthic parasites modulate the host immune response, resulting in protection against autoimmune disease but also increased susceptibility to pathogen infection. The underlying mechanisms remain largely unknown.ResultsWe showed that the type 2 immune response to enteric Nippostrongylus brasiliensis infection in mice was associated with altered intestinal mucin and AMP expression and shifts in microbiota composition. Most strikingly, infection reduced concentrations of intestinal segmented filamentous bacteria (SFB), known inducers of T helper 17 cells, and IL-17-associated gene expression. Infected mice deficient in IL-13 or STAT6 did not reduce SFB or IL-17, and exogenous IL-25 replicated the effects of parasite infection in wild type mice.ConclusionsOur data show that parasite infection acts through host type 2 immunity to reduce intestinal SFB and expression of IL-17, providing an example of a microbiota-dependent immune modulation by parasites.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-015-0103-8) contains supplementary material, which is available to authorized users.

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f Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri. Genetic deletion of IL-25 (IL-25 ؊/؊ ) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25 ؊/؊ mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25 ؊/؊ mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.A lthough studies using mouse models have advanced our understanding of the molecular and cellular mechanisms underlying host protection against nematode infection, many of the details remain to be fully elucidated. Infection with gastrointestinal nematode parasites induces a polarized Th2 immune response featuring elevated levels of production of interleukin-4 (IL-4), IL-5, and IL-13. IL-4 and IL-13 activate STAT6 signaling pathways, leading to characteristic alterations in intestinal function that facilitate worm expulsion. IL-25, also called IL-17E, is a cytokine member of the IL-17 family that includes IL-17A through IL-17F. Unlike other members of the IL-17 family that are involved in various inflammatory pathologies, IL-25 possesses immune-modulating properties that inhibit Th1/Th17-associated inflammation.It has been observed that intestinal epithelium-derived IL-25 plays a pivotal role in the initiation of the host protective immune cascade against nematode infection. In particular, intestinal epithelial tuft cells produce IL-25 (1, 2) in response to early-stage worm infection, leading to the expansion and activation of type 2 innate lymphoid cells (ILC2), a recently identified noncytotoxic innate lymphoid cell (ILC) family member that has a classic lymphoid cell morphology but that lacks the expression of cell surface markers of other known immune lymphocytes (3, 4). The activated ILC2 then release Th2-associated cytokines IL-5 a...

Background: Bilateral renal agenesis (BRA) is a lethal congenital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios upon fetal ultrasonography reveals BRA. Although exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics cannot pick up many clinical cases. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia. Methods: A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy due to suspicion of BRA. Whole-exome sequencing-(WES)-:based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype. Results: WES and evaluation of homozygous regions in II-3 and II-4 revealed a pathological homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype. Conclusions: A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.