Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation.

Autor:	Kummerlowe C; Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Mwakamui S; Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia., Hughes TK; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Mulugeta N; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Mudenda V; Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia., Besa E; Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia., Zyambo K; Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia., Shay JES; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Fleming I; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Vukovic M; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Doran BA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Pathology, MGH, Harvard Medical School, Boston, MA 02115, USA., Aicher TP; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Wadsworth MH 2nd; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Bramante JT; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Department of Pathology, MGH, Harvard Medical School, Boston, MA 02115, USA.; University of Washington School of Medicine, Seattle, WA 98195, USA., Uchida AM; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.; Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Fardoos R; Africa Health Research Institute, Durban 4001, South Africa., Asowata OE; Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.; Africa Health Research Institute, Durban 4001, South Africa.; Center for Biomedical Research, Population Council, Rockefeller University, New York, NY 10065, USA., Herbert N; Africa Health Research Institute, Durban 4001, South Africa., Yilmaz ÖH; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Pathology, MGH, Harvard Medical School, Boston, MA 02115, USA., Kløverpris HN; Africa Health Research Institute, Durban 4001, South Africa.; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4041, South Africa.; Department of Immunology and Microbiology, University of Copenhagen, 1017 Copenhagen K, Denmark.; University College London, Division of Infection and Immunity, London WC1E 6BT, UK., Garber JJ; Department of Pathology, MGH, Harvard Medical School, Boston, MA 02115, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Ordovas-Montañes J; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.; Harvard Stem Cell Institute, Cambridge, MA 02138, USA., Gartner ZJ; University of California San Francisco, San Francisco, CA 94185, USA.; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA., Wallach T; Department of Pediatrics, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA., Shalek AK; Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA., Kelly P; Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia.; Blizard Institute, Queen Mary University of London, London E1 2AT, UK.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2022 Aug 31; Vol. 14 (660), pp. eabi8633. Date of Electronic Publication: 2022 Aug 31.
DOI:	10.1126/scitranslmed.abi8633
Abstrakt:	Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells-a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention.
Databáze:	MEDLINE
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