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

Abstract

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.

Keywords: cellular immunity; helminth; myeloid cells; trained immunity; vaccine.

Figure 1

Myeloid cells kill helminths by releasing toxic compounds or by trapping them. Myeloid cells can kill helminths directly by secreting toxic compounds. In nematodes such as Hpb, toxic compounds released by myeloid cells, such as putrescine or elastase, can act directly on the parasite cuticle (c), increasing its permeability to viability dyes (such as trypan blue or Sytox Green™) and reducing parasite motility. In trematodes, such as S. mansoni, the tegument structure (t) can be affected by neutrophils and eosinophils, as shown by TEM analysis (55). The appearance of dark pigmentation and vesicles under the apical membrane (am) and before the muscle layer (m) was reported after neutrophil and eosinophil binding. The spine area may also be affected, with a clear “bubble“ area reported around some spines (s). l, lumen; h, hypodermis; t, tegument; m, muscle cells; am, apical membrane; Mc, membranocalyx plasma membrane; b, “bubble” area; p, pigment; v, vesicles; TEM, transmission electron microscopy. Another key mechanism of helminth trapping is either by granuloma formation or by extracellular trap formation (ETosis). Trapping provides a way of immobilizing parasites causing food deprivation, stress, and the formation of a potentially toxic microenvironment. Extracellular traps have recently been reported in response to many helminths and can be formed by neutrophils, macrophages, and eosinophils, among other cells. The proteins that decorate the traps are likely to be dependent on the cell types and activation phenotypes of the myeloid cells involved. Physical trapping and close proximity to toxic molecules have been shown to result in larval death. Trapping can also take the form of granulomas, the composition of which varies between helminth species. Typically, type 2 granulomas are rich in macrophages and eosinophils, and occasionally, in neutrophils. Granulomas are usually surrounded by structural cells such as epithelial cells and fibroblasts. Their role remains poorly understood. Figure created using BioRender.com.

Figure 2

Helminths can immunomodulate myeloid cells to avoid killing. Myeloid cells are particular targets of helminth parasite evasion. Of note is that many ES products have been shown to trigger regulatory phenotypes in DCs and in macrophages, allowing the long-term survival of helminths in their hosts. Many of these immunomodulatory compounds are secreted and can be proteins, metabolites, nucleic acids, EVs, etc. It should be noted that the effects of these products are always ambiguous, as they can trigger both tolerance and regulatory mechanisms, in addition to pro-killing mechanisms (Th2 polarization induced by Sm or Nb products for example through DC activation or the hookworm factor ASP-2, which favors neutrophil migration). Given a large number of evasion molecules, only a few will be presented. Understanding this complex immunomodulation is required for efficient vaccine design, and this figure highlights how myeloid cells are central to this strategy. Ac, Ancylostoma caninum; Av, Acanthocheilonema viteae; Bm, Brugia malayi; Fhe, Fasciola hepatica; Hpb, Heligmosomoides polygyrus bakeri; Na, Necator americanus; Nb, Nippostrongylus brasiliensis; Sj, Schistosoma japonicum; Sm, Schistosoma mansoni, Of, Opisthorchis felineus, Ov, Opisthorchis viverrini; Tm, Trichuris muris; Tp, Trichinella pseudospiralis; Tsp, Trichinella spiralis, Tsu, Trichuris suis. Ag, antigen; AIP, anti-inflammatory protein; ASP-2, aspartic protease 2; CB1, cannabinoid receptor type 1; CkBP, chemokine-binding protein; CBP, cathepsin B-like protein; NiF, neutrophil inhibitory factor; eCL1, extender of the chronological lifespan protein 1; ES, excretory/secretory products; EVs, extracellular vesicles; GDH, glutamate dehydrogenase; GST, glutathione S-transferase; IL, interleukin; LEC-2, lectin 2; PGD2, prostaglandin D₂; PGE2, prostaglandin E₂; KI-1, Kunitz-type serine protease inhibitor; TPX2, thioredoxin peroxidase 2; TrxR, thioredoxin reductase. Figure created using BioRender.com.

Figure 3

Next-generation anthelmintic vaccine: A combination of a trained immunity vaccine and a traditional antigen-based vaccine. Traditional vaccines based on parenteral antigen administration cause the development of humoral immune responses that are highly specific to the pathogen targeted (in blue). In the context of helminth infection, low T-cell activation and proliferation is a cause of concern for poor antibody responses. Trained immunity-based vaccines are based on the “education” of innate immune cells that would trigger a quick response to the same or a heterologous infection (in red). This response is however unspecific. In the context of helminth infections, the right “priming” of myeloid cells could lead to (i) an increase in effector mechanisms mediated by myeloid cells, and (ii) a “rewiring” of antigen-presenting cells (APCs) and restoration of a T-cell balance in favor of Th2 (by decreasing Treg counts), which would ultimately enhance antibody production if used in combination with a traditional vaccine approach. Figure created using BioRender.com.