How to train your myeloid cells: a way forward for helminth vaccines?

Soil-transmitted helminths affect approximately 1.5 billion people worldwide. However, as no vaccine is currently available for humans, the current strategy for elimination as a public health problem relies on preventive chemotherapy. Despite more than 20 years of intense research effort, the development of human helminth vaccines (HHVs) has not yet come to fruition. Current vaccine development focuses on peptide antigens that trigger strong humoral immunity, with the goal of generating neutralizing antibodies against key parasite molecules. Notably, this approach aims to reduce the pathology of infection, not worm burden, with only partial protection observed in laboratory models. In addition to the typical translational hurdles that vaccines struggle to overcome, HHVs face several challenges (1): helminth infections have been associated with poor vaccine responses in endemic countries, probably due to the strong immunomodulation caused by these parasites, and (2) the target population displays pre-existing type 2 immune responses to helminth products, increasing the likelihood of adverse events such as allergy or anaphylaxis. We argue that such traditional vaccines are unlikely to be successful on their own and that, based on laboratory models, mucosal and cellular-based vaccines could be a way to move forward in the fight against helminth infection. Here, we review the evidence for the role of innate immune cells, specifically the myeloid compartment, in controlling helminth infections. We explore how the parasite may reprogram myeloid cells to avoid killing, notably using excretory/secretory (ES) proteins and extracellular vesicles (EVs). Finally, learning from the field of tuberculosis, we will discuss how anti-helminth innate memory could be harnessed in a mucosal-trained immunity-based vaccine

The Chemokine CXCL12 Is Essential for the Clearance of the Filaria Litomosoides sigmodontis in Resistant Mice

Litomosoides sigmodontis is a cause of filarial infection in rodents. Once infective larvae overcome the skin barrier, they enter the lymphatic system and then settle in the pleural cavity, causing soft tissue infection. The outcome of infection depends on the parasite's modulatory ability and also on the immune response of the infected host, which is influenced by its genetic background. The goal of this study was to determine whether host factors such as the chemokine axis CXCL12/CXCR4, which notably participates in the control of immune surveillance, can influence the outcome of the infection. We therefore set up comparative analyses of subcutaneous infection by L. sigmodontis in two inbred mouse strains with different outcomes: one susceptible strain (BALB/c) and one resistant strain (C57BL/6). We showed that rapid parasite clearance was associated with a L. sigmodontis-specific CXCL12-dependent cell response in C57BL/6 mice. CXCL12 was produced mainly by pleural mesothelial cells during infection. Conversely, the delayed parasite clearance in BALB/c mice was neither associated with an increase in CXCL12 levels nor with cell influx into the pleural cavity. Remarkably, interfering with the CXCL12/CXCR4 axis in both strains of mice delayed filarial development, as evidenced by the postponement of the fourth molting process. Furthermore, the in vitro growth of stage 4 filariae was favored by the addition of low amounts of CXCL12. The CXCL12/CXCR4 axis thus appears to have a dual effect on the L. sigmodontis life cycle: by acting as a host-cell restriction factor for infection, and as a growth factor for worms

Exploiting Old Pathogens to Create New Therapeutics

Intestinal worms are well known for their potent immuno-modulatory capacity. In a recent study, Navarro et al. (2016) identify a secreted hookworm protein that can suppress allergic responses in both mice and humans. This represents an exciting strategy for treating chronic inflammatory disorders such as allergy

Mécanismes de contrôle de la survie, du développement et de la reproduction de la filaire Litomosoides sigmodontis dans plusieurs souches de souris ayant des profils d'infection différents

Les filarioses affectent plus de 150 millions d individus. Le profil de manifestations cliniques est très variable allant d individus amicrofilariens présentant une pathologie importante, à des individus ne présentant aucun signe clinique, mais riches en microfilaires. L. sigmodontis se développe de façon plus ou moins complète en fonction des lignées de souris : les BALB/c permettent le développement complet du parasite; les CBA/Ca permettent un développement jusqu au stade adulte, mais sans production de microfilaires; et les C57BL/6 détruisent le parasite précocement. Ces modèles permettent l étude des mécanismes immunitaires impliqués dans le contrôle de la survie, du développement et de la reproduction des filaires. Chez des souris C57BL/6, le blocage de l axe CXCL12/CXCR4 augmente la survie du parasite, mais limite le développement filarien. Cette étude nous a permis d identifier les cellules mésothéliales pleurale, comme nouvel acteur de la réponse contre L. sigmodontis, de par leur rôle de production de CXCL12. L importance de l axe CXCL12/CXCR4 dans le succès parasitaire a été confirmée chez des souris WHIM, mutantes pour CXCR4. Chez des souris CBA/Ca, les anomalies de développement affectent le système reproducteur, bloquant l embryogénèse. La cavité pleurale de ces souris est le siège d une réaction inflammatoire importante, qui pourrait impliquer Wolbachia. La persistance de la microfilarémie après inoculation de microfilaires chez les souris CBA/Ca est très brève. Une technique de quantification des microfilaires tissulaires par qPCR a permis d établir que les microfilaires sont accumulées dans les poumons, le foie et la rate pour destructionPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Only Two Can Tango: Mast Cells Displace Epithelial Cells to Dance with ILC2s

Mast cells have been implicated in protective immunity to helminth infection, but the precise mechanism remains unclear. In this issue of Immunity, Shimokawa et al., 2017 report that mast cells are a bridge linking dying epithelial cells with effector type 2 innate lymphoid cells

Neuronal regulation of type 2 innate lymphoid cells via neuromedin U

Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis1, and are activated by host-derived cytokines and alarmins1. Discrete subsets of immune cells integrate nervous system cues2, 3, 4, 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

ILC2s and T cells cooperate to ensure maintenance of M2 macrophages for lung immunity against hookworms

This article is free to read on the publishers website 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

Secreted proteomes of different developmental stages of the gastrointestinal nematode Nippostrongylus brasiliensis

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 their similar life cycles and ease of maintenance in laboratory rodents. Adult N. brasiliensis, like the human hookworm, live in the intestine of the host and release 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 host's immune response. Phylogenetic analyses of defined protein families and global gene similarity analyses showed that N. brasiliensis is more closely related to human hookworm than are other model nematodes including the murine gastrointestinal parasite Heligmosomoides polygyrus. These findings validate the use of N. brasiliensis as a suitable parasite for the study of human hookworm infections in a tractable animal model