title: Allele-specific induction of IL-1β expression by C/EBPβ and PU.1 contributes to increased tuberculosis susceptibility.
abstract: Mycobacterium tuberculosis infection is associated with a spectrum of clinical outcomes, from long-term latent infection to different manifestations of progressive disease. Pro-inflammatory pathways, such as those controlled by IL-1β, have the contrasting potential both to prevent disease by restricting bacterial replication, and to promote disease by inflicting tissue damage. Thus, the ultimate contribution of individual inflammatory pathways to the outcome of M. tuberculosis infection remains ambiguous. In this study, we identified a naturally-occurring polymorphism in the human IL1B promoter region, which alters the association of the C/EBPβ and PU.1 transcription factors and controls Mtb-induced IL-1β production. The high-IL-1β expressing genotype was associated with the development of active tuberculosis, the severity of pulmonary disease and poor treatment outcome in TB patients. Higher IL-1β expression did not suppress the activity of IFN-γ-producing T cells, but instead correlated with neutrophil accumulation in the lung. These observations support a specific role for IL-1β and granulocytic inflammation as a driver of TB disease progression in humans, and suggest novel strategies for the prevention and treatment of tuberculosis.
authors.affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China.
authors.forename: Boping
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shaoyuan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yue
authors.affiliation: Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Chest Surgery, Shenzhen People's Hospital, Jinan University, Shenzhen, China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Senlin
authors.initials: S
authors.lastname: Zhan
authors.affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Wenfei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Liao
authors.affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Gucheng
authors.initials: G
authors.lastname: Zeng
authors.affiliation: Department of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sassetti
authors.affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Chen
mesh_terms: D000483:Alleles; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics*; D002460:Cell Line; D004198:Disease Susceptibility / Q000382:microbiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics*; D008168:Lung / Q000382:microbiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014376:Tuberculosis / Q000382:microbiology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D007371:Interferon-gamma; D053583:Interleukin-1beta; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1