Nickel Dittrich1, Luis C Berrocal-Almanza2, Shruthi Thada3, Surabhi Goyal4, Hortense Slevogt5, Gaddam Sumanlatha6, Abid Hussain7, Saubashya Sur8, Sanne Burkert9, Djin-Ye Oh10, Vijayalakshmi Valluri11, Ralf R Schumann12, Melanie L Conrad13. 1. Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: nickel.dittrich@charite.de. 2. Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: luiscabe@gmail.com. 3. Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany; Bhagwan Mahavir Medical Research Centre, Hyderabad, India. Electronic address: shruthi.thada@gmail.com. 4. Bhagwan Mahavir Medical Research Centre, Hyderabad, India; Septomics Research Center, Jena University Hospital, Jena, Germany. Electronic address: surabhi3goel@gmail.com. 5. Septomics Research Center, Jena University Hospital, Jena, Germany. Electronic address: Hortense.Slevogt@med.uni-jena.de. 6. Bhagwan Mahavir Medical Research Centre, Hyderabad, India. Electronic address: sumanlathag@yahoo.com. 7. Bhagwan Mahavir Medical Research Centre, Hyderabad, India. Electronic address: mdabid19@gmail.com. 8. Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: saubashya.sur@charite.de. 9. Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: sanne.burkert@charite.de. 10. 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. 11. Blue Peter Public Health & Research Centre, Hyderabad, India. Electronic address: vijayavalluri@hotmail.com. 12. Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: ralf.schumann@charite.de. 13. Institute for Microbiology and Hygiene, Charité-Universitätsmedizin, Berlin, Germany; Department of Psychosomatic Medicine, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: conradml@gmail.com.
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. CONCLUSION: SNP TLR1-248N is associated with TB protection in an Indian population and exhibits an increased immune response to MTB lysate in vitro.
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. CONCLUSION: SNP TLR1-248N is associated with TB protection in an Indian population and exhibits an increased immune response to MTB lysate in vitro.
Authors: Simone J C F M Moorlag; Nargis Khan; Boris Novakovic; Eva Kaufmann; Trees Jansen; Reinout van Crevel; Maziar Divangahi; Mihai G Netea Journal: Cell Rep Date: 2020-05-19 Impact factor: 9.423