Deficiency in the glycosyltransferase Gcnt1 increases susceptibility to tuberculosis through a mechanism involving neutrophils

Kaori L. Fonseca, Ana Raquel Maceiras, Rita Matos, Luisa Simoes-Costa, Jeremy Sousa, Baltazar Cá, Leandro Barros, Ana Isabel Fernandes, Stefan Mereiter, Ricardo Reis, Joana Gomes, Gustavo Tapia, Paula Rodríguez-Martínez, Montse Martín-Céspedes, Sergo Vashakidze, Shota Gogishvili, Keti Nikolaishvili, Rui Appelberg, Fátima Gärtner, Pedro N.S. RodriguesCristina Vilaplana, Celso A. Reis, Ana Magalhães*, Margarida Saraiva

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Modulation of immunity and disease by glycans is increasingly recognized. However, how host glycosylation shapes and is shaped by tuberculosis remains poorly understood. We show that deficiency in the glucosaminyl (N-acetyl) transferase 1 (Gcnt1), a key enzyme for core-2 O-glycans biosynthesis, drives susceptibility to Mycobacterium tuberculosis infection. The increased susceptibility of Gcnt1 deficient mice was characterized by extensive lung immune pathology, mechanistically related to neutrophils. Uninfected Gcnt1 deficient mice presented bone marrow, blood and lung neutrophilia, which further increased with infection. Blood neutrophilia required Gcnt1 deficiency in the hematopoietic compartment, relating with enhanced granulopoiesis, but normal cellular egress from the bone marrow. Interestingly, for the blood neutrophilia to translate into susceptibility to M. tuberculosis infection, Gnct1 deficiency in the stroma was also necessary. Complete Gcnt1 deficiency associated with increased lung expression of the neutrophil chemoattractant CXCL2. Lastly, we demonstrate that the transcript levels of various glycosyltransferase-encoding genes were altered in whole blood of active tuberculosis patients and that sialyl Lewis x, a glycan widely present in human neutrophils, was detected in the lung of tuberculosis patients. Our findings reveal a previously unappreciated link between Gcnt1, neutrophilia and susceptibility to M. tuberculosis infection, uncovering new players balancing the immune response in tuberculosis.

Original languageAmerican English
Pages (from-to)836-848
Number of pages13
JournalMucosal Immunology
Volume13
Issue number5
DOIs
Publication statusPublished - 1 Sep 2020

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