TY - JOUR
T1 - Dissemination of Mycobacterium tuberculosis is associated to a SIGLEC1 null variant that limits antigen exchange via trafficking extracellular vesicles
AU - Benet, Susana
AU - Gálvez, Cristina
AU - Drobniewski, Francis
AU - Kontsevaya, Irina
AU - Arias, Lilibeth
AU - Monguió-Tortajada, Marta
AU - Erkizia, Itziar
AU - Urrea, Victor
AU - Ong, Ruo-Yan
AU - Luquin, Marina
AU - Dupont, Maeva
AU - Chojnacki, Jakub
AU - Dalmau, Judith
AU - Cardona, Paula
AU - Neyrolles, Olivier
AU - Lugo-Villarino, Geanncarlo
AU - Vérollet, Christel
AU - Julián, Esther
AU - Furrer, Hansjakob
AU - Günthard, Huldrych F.
AU - Crocker, Paul R.
AU - Tapia, Gustavo
AU - Borràs, Francesc E.
AU - Fellay, Jacques
AU - McLaren, Paul J.
AU - Telenti, Amalio
AU - Cardona, Pere-Joan
AU - Clotet, Bonaventura
AU - Vilaplana, Cristina
AU - Martinez-Picado, Javier
AU - Izquierdo-Useros, Nuria
N1 - Javier Martinez-Picado and Nuria Izquierdo-Useros are supported by the Spanish Secretariat of State of Research, Development
and Innovation (SEIDI) through grant SAF2016-80033-R. Javier Martinez-Picado is supported by PID2019-109870RB-I00. This
research was sponsored in part by Grifols and by CERCA Programme/Generalitat de Catalunya 2017 SGR 252. The genetic analyses were realized within the framework of the Swiss HIV Cohort Study (SHCS Project number 747), which is supported by the
Swiss National Science Foundation (Grant Number 177499) and by the SHCS research foundation. Susana Benet is supported
by the Rio Hortega programme funded by the Spanish Health Institute Carlos III (No. CM17/00242). Cristina Gálvez is supported by the PhD fellowship of the Spanish Ministry of Education, Culture and Sport (FPU15/03698). Francis Drobniewski is
supported by the Imperial Biomedical Research Center and by Horizon 2020 grant No. 825673 CARE: Common Action Against
HIV/TB/HCV Across the Regions of Europe. Irina Kontsevaya is also supported by Horizon 2020 CARE grant No. 825673, grant
No. 733079 (AnTBiotic: progressing TB drug candidates to clinical proof of concept) and grant No. RIA2017T-2030 (CLICK-TB:
Novel Clinical Candidates to Kill TB). Jakub Chojnacki is supported by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 793830. Lilibeth Arias is supported by the European
Commission Horizon 2020 research and innovation program under grant agreement TBVAC2020 No. 643381. Paula Cardona
and Cristina Vilaplana are supported by the Plan Nacional I + D + I co-financed by ISCIII-Subdirección General de Evaluación and Fondo-EU de Desarrollo Regional (FEDER) through IFI14/00015 and CPII18/00031. Lilibeth Arias, Paula Cardona,
Pere-Joan Cardona and Cristina Vilaplana are supported by the Catalan Agency for Management of University and Research
Grants (AGAUR 2017 SGR500). Geanncarlo Lugo-Villarino and Christel Vérollet are supported by the ANRS 2020–1 grant.
Marta Monguió-Tortajadaand Francesc E. Borràs are founded by SGR programmes (2017-SGR-301 REMAR Group, and 2017-
SGR-483 ICREC Group) from the Generalitat de Catalunya. Francesc E. Borràs is a researcher from Fundació Institut de Recerca
en Ciències de la Salut Germans Trias i Pujol, supported by the Health Department of the Catalan Government (Generalitat de
Catalunya). Marina Luquin and Esther Julián are supported by AGAUR grant (2017 SGR-229). Paul R. Crocker was supported
by the Wellcome Trust grant 103744/Z/14/Z
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Extracellular vesicles
KW - HIV-1
KW - Mtb
KW - Siglec-1
UR - http://www.scopus.com/inward/record.url?scp=85099849253&partnerID=8YFLogxK
U2 - 10.1002/jev2.12046
DO - 10.1002/jev2.12046
M3 - Article
C2 - 33489013
SN - 2001-3078
VL - 10
JO - Journal of Extracellular Vesicles
JF - Journal of Extracellular Vesicles
IS - 3
M1 - e12046
ER -
