Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection.

BACKGROUND Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI. METHODS We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication. RESULTS In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy. CONCLUSIONS These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes.

[1]  Mahavir Singh,et al.  Genetic Regulation of Acquired Immune Responses to Antigens ofMycobacterium tuberculosis: a Study of Twins in West Africa , 2001, Infection and Immunity.

[2]  J. Casanova,et al.  Genetic dissection of immunity to mycobacteria: the human model. , 2002, Annual review of immunology.

[3]  V. Deretic,et al.  Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages , 2004, Cell.

[4]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[5]  A. Viera,et al.  Understanding interobserver agreement: the kappa statistic. , 2005, Family medicine.

[6]  V. Deretic,et al.  Human IRGM Induces Autophagy to Eliminate Intracellular Mycobacteria , 2006, Science.

[7]  L. Zhao,et al.  A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. , 2006, The Journal of infectious diseases.

[8]  Giorgio Sirugo,et al.  A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis , 2007, Nature Genetics.

[9]  T. Hawn,et al.  Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter? , 2007, Immunological reviews.

[10]  S. Nejentsev,et al.  Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis , 2008, PLoS genetics.

[11]  Cheryl L. Thompson,et al.  Genome Scan of M. tuberculosis Infection and Disease in Ugandans , 2008, PloS one.

[12]  K. Lunetta.  Genetic Association Studies , 2008, Circulation.

[13]  Gabriel Silva,et al.  Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America , 2009, Human mutation.

[14]  J. Casanova,et al.  Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis , 2009, The Journal of experimental medicine.

[15]  S. Niemann,et al.  Autophagy Gene Variant IRGM −261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains , 2009, PLoS pathogens.

[16]  S. Niemann,et al.  IL10 Haplotype Associated with Tuberculin Skin Test Response but Not with Pulmonary TB , 2009, PloS one.

[17]  Sarman Singh,et al.  Genome-wide Analysis of the Host Intracellular Network that Regulates Survival of Mycobacterium tuberculosis , 2010, Cell.

[18]  A. Morris,et al.  Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2 , 2010, Nature Genetics.

[19]  F. Salzano,et al.  Cytokine genes are associated with tuberculin skin test response in a native Brazilian population. , 2010, Tuberculosis.

[20]  P. V. van Helden,et al.  High heritability of antimycobacterial immunity in an area of hyperendemicity for tuberculosis disease. , 2010, The Journal of infectious diseases.

[21]  Jian-yuan Zhang,et al.  Identification of a novel IRGM promoter single nucleotide polymorphism associated with tuberculosis. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[22]  John L. Johnson,et al.  Geographic Differences in Time to Culture Conversion in Liquid Media: Tuberculosis Trials Consortium Study 28. Culture Conversion Is Delayed in Africa , 2011, PloS one.

[23]  E. Graviss,et al.  Polymorphic Allele of Human IRGM1 Is Associated with Susceptibility to Tuberculosis in African Americans , 2011, PloS one.

[24]  Richard D. Wells,et al.  Association of Human TLR1 and TLR6 Deficiency with Altered Immune Responses to BCG Vaccination in South African Infants , 2011, PLoS pathogens.

[25]  C. Stein,et al.  Genetic Epidemiology of Tuberculosis Susceptibility: Impact of Study Design , 2011, PLoS pathogens.

[26]  F. Vannberg,et al.  Human genetic susceptibility to intracellular pathogens , 2011, Immunological reviews.

[27]  M. Oosting,et al.  Autophagy modulates the Mycobacterium tuberculosis‐induced cytokine response , 2011, Immunology.

[28]  Mycobacterium tuberculosis Triggers Host Type I IFN Signaling To Regulate IL-1β Production in Human Macrophages , 2011, The Journal of Immunology.

[29]  A. Sher,et al.  Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction , 2012, Nature Immunology.

[30]  Bachti Alisjahbana,et al.  Polymorphisms in Autophagy Genes and Susceptibility to Tuberculosis , 2012, PloS one.

[31]  V. Deretic,et al.  Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation , 2012, Proceedings of the National Academy of Sciences.

[32]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[33]  K. Mills,et al.  Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion , 2012, The Journal of Immunology.

[34]  T. P. Neufeld,et al.  ULK1 induces autophagy by phosphorylating Beclin-1 and activating Vps34 lipid kinase , 2013, Nature Cell Biology.

[35]  M. Shiloh,et al.  PARKIN ubiquitin ligase mediates resistance to intracellular pathogens , 2013, Nature.

[36]  G. Barber,et al.  Cyclic Dinucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling , 2013, Cell.

[37]  E. Schurr,et al.  Host Genomics and Control of Tuberculosis Infection , 2013, Public Health Genomics.

[38]  Paul G. Thomas,et al.  Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection , 2013, Nature Immunology.

[39]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[40]  A. Hyman,et al.  Pericentriolar material structure and dynamics , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[41]  J. Casanova,et al.  Human genetics of tuberculosis: a long and winding road , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[42]  George M. Church,et al.  CHOPCHOP: a CRISPR/Cas9 and TALEN web tool for genome editing , 2014, Nucleic Acids Res..

[43]  Richard G. White,et al.  Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings , 2014, Proceedings of the National Academy of Sciences.

[44]  Neville E. Sanjana,et al.  Improved vectors and genome-wide libraries for CRISPR screening , 2014, Nature Methods.

[45]  C. Ian,et al.  メチル化DNA結合タンパク質MBD2はグルココルチコイド受容体のNGFI-A(egr-1)媒介転写活性化を促進する , 2014 .

[46]  K. Cadwell,et al.  Ubiquilin 1 Promotes IFN-γ-Induced Xenophagy of Mycobacterium tuberculosis , 2015, PLoS pathogens.

[47]  C. Delacourt,et al.  Tuberculin Skin Test Negativity Is Under Tight Genetic Control of Chromosomal Region 11p14-15 in Settings With Different Tuberculosis Endemicities , 2014, The Journal of infectious diseases.

[48]  J. Casanova,et al.  Inherited and acquired immunodeficiencies underlying tuberculosis in childhood , 2015, Immunological reviews.

[49]  P. Moseley,et al.  Immunologic manifestations of autophagy. , 2015, The Journal of clinical investigation.

[50]  Xiong Wang,et al.  Association of autophagy-related IRGM polymorphisms with latent versus active tuberculosis infection in a Chinese population. , 2016, Tuberculosis.