The SIGLEC14 null allele is associated with Mycobacterium tuberculosis- and BCG-induced clinical and immunologic outcomes

Tuberculosis (Edinb). 2017 May:104:38-45. doi: 10.1016/j.tube.2017.02.005. Epub 2017 Feb 21.

Abstract

Humans exposed to Mycobacterium tuberculosis (Mtb) have variable susceptibility to tuberculosis (TB) and its outcomes. Siglec-5 and Siglec-14 are members of the sialic-acid binding lectin family that regulate immune responses to pathogens through inhibitory (Siglec-5) and activating (Siglec-14) domains. The SIGLEC14 coding sequence is deleted in a high proportion of individuals, placing a SIGLEC5-like gene under the expression of the SIGLEC14 promoter (the SIGLEC14 null allele) and causing expression of a Siglec-5 like protein in monocytes and macrophages. We hypothesized that the SIGLEC14 null allele was associated with Mtb replication in monocytes, T-cell responses to the BCG vaccine, and clinical susceptibility to TB. The SIGLEC14 null allele was associated with protection from TB meningitis in Vietnamese adults but not with pediatric TB in South Africa. The null allele was associated with increased IL-2 and IL-17 production following ex-vivo BCG stimulation of blood from 10 week-old South African infants vaccinated with BCG at birth. Mtb replication was increased in THP-1 cells overexpressing either Siglec-5 or Siglec-14 relative to controls. To our knowledge, this is the first study to demonstrate an association between SIGLEC expression and clinical TB, Mtb replication, or BCG-specific T-cell cytokines.

Keywords: Mycobacterium tuberculosis; SIGLEC; Tuberculosis.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Adolescent
  • Adult
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, Differentiation, Myelomonocytic / genetics
  • Antigens, Differentiation, Myelomonocytic / immunology
  • BCG Vaccine / administration & dosage*
  • BCG Vaccine / immunology
  • Case-Control Studies
  • Child, Preschool
  • Cytokines / immunology
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Host-Pathogen Interactions
  • Humans
  • Infant
  • Infant, Newborn
  • Lectins / genetics*
  • Lectins / immunology
  • Male
  • Monocytes / immunology
  • Monocytes / microbiology
  • Mycobacterium tuberculosis / growth & development
  • Mycobacterium tuberculosis / immunology*
  • Phenotype
  • Prospective Studies
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / immunology
  • South Africa
  • T-Lymphocytes / immunology
  • T-Lymphocytes / microbiology
  • THP-1 Cells
  • Time Factors
  • Treatment Outcome
  • Tuberculosis, Meningeal / genetics*
  • Tuberculosis, Meningeal / immunology
  • Tuberculosis, Meningeal / microbiology
  • Tuberculosis, Meningeal / prevention & control*
  • Tuberculosis, Pulmonary / genetics*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / prevention & control*
  • Vaccination*
  • Vietnam

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • BCG Vaccine
  • Cytokines
  • Lectins
  • Receptors, Cell Surface
  • SIGLEC14 protein, human
  • SIGLEC5 protein, human