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.
Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri