Dissemination of Mycobacterium tuberculosis is associated to a SIGLEC1 null variant that limits antigen exchange via trafficking extracellular vesicles

Susana Benet, Cristina Gálvez, Francis Drobniewski, Irina Kontsevaya, Lilibeth Arias, Marta Monguió-Tortajada, Itziar Erkizia, Victor Urrea, Ruo-Yan Ong, Marina Luquin, Maeva Dupont, Jakub Chojnacki, Judith Dalmau, Paula Cardona, Olivier Neyrolles, Geanncarlo Lugo-Villarino, Christel Vérollet, Esther Julián, Hansjakob Furrer, Huldrych F. GünthardPaul R. Crocker, Gustavo Tapia, Francesc E. Borràs, Jacques Fellay, Paul J. McLaren, Amalio Telenti, Pere-Joan Cardona, Bonaventura Clotet, Cristina Vilaplana, Javier Martinez-Picado, Nuria Izquierdo-Useros

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Abstract

The identification of individuals with null alleles enables studying how the loss of gene function affects infection. We previously described a non-functional variant in SIGLEC1, which encodes the myeloid-cell receptor Siglec-1/CD169 implicated in HIV-1 cell-to-cell transmission. Here we report a significant association between the SIGLEC1 null variant and extrapulmonary dissemination of Mycobacterium tuberculosis (Mtb) in two clinical cohorts comprising 6,256 individuals. Local spread of bacteria within the lung is apparent in Mtb-infected Siglec-1 knockout mice which, despite having similar bacterial load, developed more extensive lesions compared to wild type mice. We find that Siglec-1 is necessary to induce antigen presentation through extracellular vesicle uptake. We postulate that lack of Siglec-1 delays the onset of protective immunity against Mtb by limiting antigen exchange via extracellular vesicles, allowing for an early local spread of mycobacteria that increases the risk for extrapulmonary dissemination.

Original languageEnglish
Article numbere12046
Number of pages17
JournalJournal of Extracellular Vesicles
Volume10
Issue number3
Early online date14 Jan 2021
DOIs
Publication statusPublished - Jan 2021

Keywords

  • Extracellular vesicles
  • HIV-1
  • Mtb
  • Siglec-1

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