Factors Regulating Murine Tuft cell Hyperplasia in the Small Intestine during Infection with Hymenolepis Diminuta
Authors: Rajeev Sruthi , Defaye Manon , Shute Adam , Wang Arthur , Wang Susan , Altier Christophe , McKay Derek Mark 
Published: April 2020

Introduction

At homeostasis, tuft cells form a rare epithelial cell population in the intestine. During parasitic infections with nematodes, the tuft cell has been shown to mobilize innate lymphoid type 2 cells (ILC2) by releasing the alarmin cytokine IL‐25. Enteric tuft cells possess key elements of the taste receptor pathway and may be luminal sensors of parasitic infections. Hymenolepis diminuta is a rat tapeworm that is rapidly expelled when introduced in immunocompetent murine hosts. During infection with this non‐abrasive, lumen dwelling parasite, immunocompetent mice display dramatic tuft cell hyperplasia across the small intestine. The factors regulating tuft cell response in this cestode model of infection are poorly understood. As observed in the nematode model of infection, we previously showed that tuft cell hyperplasia in response to H. diminuta is dependent on IL‐4 receptor mediated signalling. The influence of the adaptive immune system, which partakes in immunity against H. diminuta, was yet to be understood. Helminth infections are accompanied by alterations in the composition of the microbiota and may contribute to important luminal influences. Finally, it is poorly understood if tuft cell hyperplasia is regulated by changes in the sensory‐motor functions of the gut during helminth infection.

Aims

To test if mice lacking (1) a functional adaptive immune system, (2) a microbiome, and (3) TRPV1+ gut‐innervating sensory nerves display enteric tuft cell hyperplasia following infection with H. diminuta.

Methods

RAG‐1−/− (male and female) and germ‐free mice (n=3–6) were orally gavaged with 5 cysticercoids of H. diminuta. Age matched non‐infected mice served as control groups. Male C57BL/6j mice (n=3–4) were treated with resiniferatoxin (RTX) to ablate TRPV1+ sensory neurons before infection. Mid‐jejunum cryosections (10mm) or paraffin embedded sections (5mm) were immuno‐stained against doublecortin‐like kinase ‐1 (DCLK‐1), a tuft cell marker, at 5, 8, 11 and 14 days post‐infection.

Results

Wild‐type C57BL/6j mice expel H. diminuta by 11 days post infection and display ~ 10–15 fold increase in tuft cells at this time. In RAG‐1−/− mice, tuft cell hyperplasia at 11 days post‐infection was observed at a lesser magnitude than wild type mice. Germ‐free mice displayed tuft cell hyperplasia and kinetics of worm expulsion that were not different from wild‐type mice. RTX‐treated mice with confirmed loss of TRPV1+ nerve fibers in the gut and their cell soma in the dorsal root and nodose ganglia, had a greater increase (~2‐fold) in tuft cell numbers compared to the untreated infected wild‐type mice at day 11 post infection.

Conclusion

In the H. diminuta‐ mouse model system, we find that tuft cell hyperplasia is largely, but not entirely dependent on adaptive immunity and occurs independent of the gut microbiota. The observation that TRPV1+ sensory nerves appear to contribute to regulation of tuft cell hyperplasia warrants further study on tuft cell‐sensory nerve interactions.

Support or Funding Information

NSERC, CIHR, Henry Koopman Memorial Entrance Scholarship in Gastrointestinal Nutrition, Metabolism and Inflammation