Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis, and are activated by host-derived cytokines and alarmins. Discrete subsets of immune cells integrate nervous system cues, but it remains unclear whether neuron-derived signals control ILC2s. Here we show that neuromedin U (NMU) in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron-ILC2 unit. We found that ILC2s selectively express neuromedin U receptor 1 (Nmur1), and mucosal neurons express NMU. Cell-autonomous activation of ILC2s with NMU resulted in immediate and strong NMUR1-dependent production of innate inflammatory and tissue repair cytokines. NMU controls ILC2s downstream of extracellular signal-regulated kinase and calcium-influx-dependent activation of both calcineurin and nuclear factor of activated T cells (NFAT). NMU treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines. Our work reveals that neuron-ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses.

Defining the immune mechanisms underlying protective immunity to helminth infection remains an important challenge. Here we report that lung CD4⁺ T cells and Group 2 innate lymphoid cells (ILC2s) work in concert to block Nippostrongylus brasiliensis (Nb) development in the parenchyma within 48 h in mice. Immune-damaged larvae have a striking morphological defect that is dependent on the expansion of IL-13-producing ILC2 and CD4⁺ T cells, and the activation of M2 macrophages. This T-cell requirement can be bypassed by administration of IL-2 or IL-33, resulting in expansion of IL-13-producing ILC2s and larval killing. Depletion of ILC2s inhibits larval killing in IL-2-treated mice. Our results broaden understanding of ILC2’s role in immunity to helminths by demonstrating that they not only act as alarmin sensors, but can also be sustained by CD4⁺ T cells, ensuring both the prompt activation and the maintenance of IL-13-dependent M2 macrophage immunity in the lung.

Hookworms infect more than 700 million people worldwide and cause more morbidity than most other human parasitic infections. Nippostrongylus brasiliensis (the rat hookworm) has been used as an experimental model for human hookworm because of its similar life cycle and ease of maintenance in laboratory rodents. Adult N. brasiliensis, like the human hookworm, lives in the intestine of the host and releases excretory/secretory products (ESP), which represent the major host-parasite interface. We performed a comparative proteomic analysis of infective larval (L3) and adult worm stages of N. brasiliensis to gain insights into the molecular bases of host-parasite relationships and determine whether N. brasiliensis could indeed serve as an appropriate model for studying human hookworm infections. Proteomic data were matched to a transcriptomic database assembled from 245,874,892 Illumina reads from different developmental stages (eggs, L3, L4, and adult) of N. brasiliensis yielding∼18,426 unigenes with 39,063 possible isoform transcripts. From this analysis, 313 proteins were identified from ESPs by LC-MS/MS—52 in the L3 and 261 in the adult worm. Most of the proteins identified in the study were stage-specific (only 13 proteins were shared by both stages); in particular, two families of proteins—astacin metalloproteases and CAP-domain containing SCP/TAPS—were highly represented in both L3 and adult ESP. These protein families are present in most nematode groups, and where studied, appear to play roles in larval migration and evasion of the host9s immune response. Phylogenetic analyses of defined protein families and global gene similarity analyses showed that N. brasiliensis has a greater degree of conservation with human hookworm than other model nematodes examined. These findings validate the use of N. brasiliensis as a suitable parasite for the study of human hookworm infections in a tractable animal model.

Symbiotic associations between eukaryotes and microorganisms are frequently observed in nature, and range along the continuum between parasitism and mutualism. The genus Wolbachia contains well-known intracellular bacteria of arthropods that induce several reproductive phenotypes that benefit the transmission of the bacteria. Interestingly, Wolbachia bacteria have been found in the Onchocercidae, a family of filarial nematodes, including species that cause human filarial diseases, e.g. lymphatic filariasis and onchocerciasis. The endosymbiont is thought to be mutualistic in the Onchocercidae, and to provide essential metabolites to the filariae. Currently, Wolbachia bacteria are targets of antibiotic therapy with tetracyclines, which have profound effects on the development, viability and fertility of filarial parasites. This overview article presents the Onchocercidae and Wolbachia, and then discusses the origin and the nature of the symbiosis. It highlights the contribution of Wolbachia to the survival of the filariae and to the development of pathology. Finally, the infection control implications for filariases are debated. Potential directions for future research are also discussed.

Helminths are credited with being the major selective force driving the evolution of the so called “type 2” immune responses in vertebrate animals, with their size and infection strategies presenting unique challenges to the immune system. Originally, type 2 immune responses were defined by the presence and activities of the CD4+ T helper 2 subset producing the canonical cytokines IL-4, IL-5 and IL-13. This picture is now being challenged by the discovery of a more complex pattern of CD4+ T helper cell subsets that appear during infection, including Tregs, Th17, Tfh and more recently Th22, Th9, and ThGM. In addition, a clearer view of the mechanisms by which helminths and their products selectively prime the CD4+ T cell subsets is emerging. In this review, we have focused on recent new data concerning the selective priming, differentiation and functional role of CD4+ T helper cell subsets in the context of helminth infection. We argue for a re-evaluation of the original Th2 paradigm and discuss how the observed plasticity of the T helper subsets may enable the parasitized host to achieve an appropriate compromise between elimination, tissue repair, containment and pathology.