The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells

Luzmariel Medina Sanchez; Magdalena Siller; Yanlin Zeng; Pamela H Brigleb; Kishan A Sangani; Ariadna S Soto; Clarisse Engl; Colin R Laughlin; Mohit Rana; Lauren Van Der Kraak; Surya P Pandey; Mackenzie J Bender; Britney Fitzgerald; Lee Hedden; Kay Fiske; Gwen M Taylor; Austin P Wright; Isha D Mehta; Syed A Rahman; Heather J Galipeau; Steven J Mullett; Stacy L Gelhaus; Simon C Watkins; Premysl Bercik; Timothy J Nice; Bana Jabri; Marlies Meisel; Jishnu Das; Terence S Dermody; Elena F Verdú; Reinhard Hinterleitner

doi:10.1016/j.immuni.2023.06.022

The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells

Immunity. 2023 Aug 8;56(8):1862-1875.e9. doi: 10.1016/j.immuni.2023.06.022. Epub 2023 Jul 20.

Authors

Luzmariel Medina Sanchez¹, Magdalena Siller², Yanlin Zeng³, Pamela H Brigleb⁴, Kishan A Sangani⁵, Ariadna S Soto², Clarisse Engl², Colin R Laughlin², Mohit Rana², Lauren Van Der Kraak², Surya P Pandey², Mackenzie J Bender², Britney Fitzgerald², Lee Hedden², Kay Fiske⁶, Gwen M Taylor⁶, Austin P Wright⁷, Isha D Mehta², Syed A Rahman⁸, Heather J Galipeau⁹, Steven J Mullett¹⁰, Stacy L Gelhaus¹⁰, Simon C Watkins¹¹, Premysl Bercik⁹, Timothy J Nice⁷, Bana Jabri⁵, Marlies Meisel¹², Jishnu Das⁸, Terence S Dermody¹³, Elena F Verdú⁹, Reinhard Hinterleitner¹⁴

Affiliations

¹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Graduate Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China.
⁴ Graduate Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁵ Department of Medicine, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA.
⁶ Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁷ Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA.
⁸ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁹ Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹⁰ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹ Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹² Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹³ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: reinhard@pitt.edu.

PMID: 37478853
PMCID: PMC10529081 (available on 2024-08-08)
DOI: 10.1016/j.immuni.2023.06.022

Abstract

Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.

Keywords: T helper 1; Tritrichomonas; celiac disease; dendritic cells; dietary antigen; loss of oral tolerance; microbiota; oral tolerance; regulatory T cell; reovirus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens*
Dendritic Cells
Diet
Glutens
Humans
Immune Tolerance
Immunity, Innate*
Mice

Substances

Antigens
Glutens

Abstract

Publication types

MeSH terms

Substances

Grants and funding