Leprosy and the Adaptation of Human Toll-Like Receptor 1

PLoS Pathogens

Bibhuti Saha¹  Sian Floyd²  Brendan J. Keating²  Ramasamy M. Pitchappan³  Julian C. Knight³  Adrian V. S. Hill⁴  Suchismita Roy⁵  Sarah Meisner⁵  Anna Rautanen⁶  Rameshwar N. K. Bamezai⁷  Cecilia Kim⁷  Benjamin P. Fairfax⁸  Hakon Hakonarson⁹  Paul E. M. Fine⁹  Vijay K. Garg^1,10  Rupali Chopra^1,10  Sailesh Gochhait^1,10  Dheeraj Malhotra^1,10  Fredrik O. Vannberg^1,10  Belum S. N. Reddy^1,10  Aleksey Rudko^1,10  Shafat Ali^1,11  Shweta Aggarwal^1,11  Maxim B. Freidin^1,11  Fredrik H. Pettersson^1,12  Sunil K. Hazra^1,12  Valery P. Puzyrev^1,12  Richard A. Adegbola^1,12  Tara C. Mills^1,12  Chiea C. Khor^1,12  Philip C. Hill^1,12  Sunny H. Wong^1,12  Yik Y. Teo^1,12  Amit Srivastava^1,12  Stephen J. Chapman^1,12 

[1] Bath Royal United Hospital Trust, Combe Park, Bath, United Kingdom;Calcutta School of Tropical Medicine, Kolkata, India;Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America;Centre for Excellence in Genomic Sciences, Madurai Kamaraj University, Madurai, India;Department of Dermatology and Sexually Transmitted Diseases, Maulana Azad Medical College, Lok Nayak Jai Prakash Hospital, New Delhi, India;Host Susceptibility to Infection Program, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore;Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom;Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;MRC Laboratories, Fajara, The Gambia;National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India;Research Institute of Medical Genetics, Siberian Branch of Russian Academy of Medical Sciences, Tomsk, Russia;Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

关键词: Leprosy;    Toll-like receptors;    Genetic loci;    Mycobacterium leprae;    Haplotypes;    Variant genotypes;    Alleles;    Host-pathogen interactions;   

DOI  :  10.1371/journal.ppat.1000979

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7×10−8, OR = 0.31, 95% CI = 0.20–0.48, and HLA-DQA1 rs1071630, case-control P = 4.9×10−14, OR = 0.43, 95% CI = 0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.

【 授权许可】

CC BY