Enteric Tuft Cells in Host-Parasite Interactions

Abstract

Enteric tuft cells are chemosensory epithelial cells gaining attention in the field of host-parasite interactions. Expressing a repertoire of chemosensing receptors and mediators, these cells have the potential to detect lumen-dwelling helminth and protozoan parasites and coordinate epithelial, immune, and neuronal cell defenses against them. This review highlights the versatility of enteric tuft cells and sub-types thereof, showcasing nuances of tuft cell responses to different parasites, with a focus on helminths reflecting the current state of the field. The role of enteric tuft cells in irritable bowel syndrome, inflammatory bowel disease and intestinal viral infection is assessed in the context of concomitant infection with parasites. Finally, the review presents pertinent questions germane to understanding the enteric tuft cell and its role in enteric parasitic infections. There is much to be done to fully elucidate the response of this intriguing cell type to parasitic-infection and there is negligible data on the biology of the human enteric tuft cell-a glaring gap in knowledge that must be filled.

Keywords: Th2 effector; coinfections; epithelial chemosensors; gastrointestinal disorders; helminths; protozoa.

Figure 2

Dynamics of parasite clearance, tuft cell hyperplasia and goblet cell hyperplasia during parasitic infections. In some acute enteric infections, such as with (A,B) N. brasiliensis and T. spiralis (intestinal phase) the events of enteric tuft cell (ETC) hyperplasia and goblet cell hyperplasia precede or happen around the same time as worm expulsion/reduction in worm burdens [6,8,9,80,81]. In chronic parasitic infections however, such as with (C) H. polygyrus [6,9,46,82,83], (D) the protozoan Tritrichomonas [59] and (E) E. caproni [55], ETC hyperplasia persists for as long as parasite burden persists [7,10,23] and may also coincide with goblet cell hyperplasia [7,10,56]. It remains to be tested whether ETC hyperplasia (as well as goblet cell hyperplasia) serves to either induce immunity against secondary/concomitant infections or mediate repair of damaged intestinal tissue [23]. ETC hyperplasia in parasitic models of infection may be the downstream effect of a Th2 cascade (dominated by increased IL-13 production in the intestinal niche) [9] with the exception of the (E,F) E. caproni trematode model of murine infection, where primary host response is Th1 cytokine centric [53], and ETC hyperplasia is observed in both primary infection as well as secondary infection after drug clearance (praziquantel) [10]. Graphs represent hypothetical temporal kinetics of worm burden, tuft cell and goblet cell numbers based on individual time point data presented in literature, where “?” and dotted lines represent estimation of trendlines at time points where data was unavailable.

Figure 1

Enteric tuft cells (ETCs) have been studied in murine infection models with the nematodes Heligosmoides polygyrus (1), Nippostrongylus brasiliensis (2), and Trichinella spiralis (4); the trematode Echinistoma caproni (5), and the protozoan Tritrichomonas (3). In response to helminths and protozoans, ETCs produce and release IL-25 (1-4) and cysteinyl leukotrienes (1,2), which subsequently activate the innate lymphoid cell (ILC2) population in the underlying lamina propria via IL-17RB and CYSLTR receptors to produce IL-13, IL-5 and IL-9 [6,7,9,57,64]. IL-13 induces intestinal stem cell differentiation via IL-4Rα signaling, causing ETC and goblet cell hyperplasia (see Figure 2 for approximate timelines), increased smooth muscle contractility and intestinal permeability amongst other mechanisms that aid parasite expulsion [5,9]. Mast cells sense damage related release of ATP and release IL-33 to activate ILC2 production of IL-13 (1) [43]. ILC2s also produce and release acetylcholine (ACh) in response to infection with N. brasileinsis and are activated by ACh to produce IL-13 (2) [65,66]. Although ETC hyperplasia is observed after primary and secondary infection with E. caproni, Il-25 expression is upregulated in the acute secondary infection rather than the chronic primary infection, which is characterized by increased levels of Th1 cytokine mRNA (5) [10,53,63]. ETC-derived mediators may also act on other cell types such as eosinophils and macrophages (alternatively activated macrophages, AAM), to coordinate repair, as well activate CD4 T cell populations (4,5) to release cytokines during parasitic infections [48,67,68,69].“?” represents mechanisms that are yet unknown in tuft cell literature.