title: Toll-like receptor 1 variations influence susceptibility and immune response to Mycobacterium tuberculosis.
abstract: BACKGROUND
  Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (MTB) infection, is still a global public health problem. TB susceptibility varies greatly in infected individuals, and mycobacterial recognition by the innate immune system likely affects disease course and outcome. This research describes a single nucleotide polymorphism in the Toll-like receptor (TLR) 1 gene that functionally alters the innate immune response to MTB and is associated with TB susceptibility in India.
  
  
  METHODS
  206 TB patients and 239 healthy controls from Hyderabad, India were analyzed for SNPs in the TLR1 and TLR2 genes, which were subsequently correlated to TB susceptibility. To test individual responses to MTB lysates, we stimulated PBMCs from genotyped healthy German individuals, as well as HEK cells transfected with TLR1/2 variants. TNF production and NF-kB activation were assessed respectively.
  
  
  RESULTS
  Cohort analysis associated the TLR1-248N SNP (RS4833095) with TB protection. TLR1-248N expressing PBMCs from healthy controls exhibited an increased TNF response to MTB lysates. In addition to this, functional studies using HEK cell lines transfected with TLR1-248N and stimulated with MTB showed an increased NF-kB activation.
  
  
  CONCLUSIONS
  SNP TLR1-248N is associated with TB protection in an Indian population and exhibits an increased immune response to MTB lysate in vitro.
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: nickel.dittrich@charite.de.
authors: Nickel
authors: N
authors: Dittrich
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: luiscabe@gmail.com.
authors: Luis C
authors: LC
authors: Berrocal-Almanza
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany; Bhagwan Mahavir Medical Research Centre, Hyderabad, India. Electronic address: shruthi.thada@gmail.com.
authors: Shruthi
authors: S
authors: Thada
authors: Bhagwan Mahavir Medical Research Centre, Hyderabad, India; Septomics Research Center, Jena University Hospital, Jena, Germany. Electronic address: surabhi3goel@gmail.com.
authors: Surabhi
authors: S
authors: Goyal
authors: Septomics Research Center, Jena University Hospital, Jena, Germany. Electronic address: Hortense.Slevogt@med.uni-jena.de.
authors: Hortense
authors: H
authors: Slevogt
authors: Bhagwan Mahavir Medical Research Centre, Hyderabad, India. Electronic address: sumanlathag@yahoo.com.
authors: Gaddam
authors: G
authors: Sumanlatha
authors: Bhagwan Mahavir Medical Research Centre, Hyderabad, India. Electronic address: mdabid19@gmail.com.
authors: Abid
authors: A
authors: Hussain
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: saubashya.sur@charite.de.
authors: Saubashya
authors: S
authors: Sur
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: sanne.burkert@charite.de.
authors: Sanne
authors: S
authors: Burkert
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany; Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: djin-ye.oh@childrens.harvard.edu.
authors: Djin-Ye
authors: DY
authors: Oh
authors: Blue Peter Public Health & Research Centre, Hyderabad, India. Electronic address: vijayavalluri@hotmail.com.
authors: Vijayalakshmi
authors: V
authors: Valluri
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: ralf.schumann@charite.de.
authors: Ralf R
authors: RR
authors: Schumann
authors: Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany; Department of Psychosomatic Medicine, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: conradml@gmail.com.
authors: Melanie L
authors: ML
authors: Conrad
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007194:India; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D012307:Risk Factors; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D014162:Transfection; D014376:Tuberculosis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D016328:NF-kappa B; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha
keywords: Functional analysis; India; Modeling; Mycobacterium tuberculosis; Single nucleotide polymorphism; Toll-like receptor 1