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.
Highlights
Tuberculosis (TB), a chronic bacterial disease caused by Mycobacterium tuberculosis (Mtb), remains a major global health problem that claims 1.4 million lives annually
IL-1b is important for the initial establishment of antimicrobial adaptive immunity, but prolonged IL-1b expression can cause progressive immunopathology during M. tuberculosis infection
We address the role of IL-1b-mediated inflammation using a combination of human genetics and molecular biology, and suggest that exuberant IL-1b responses are causatively associated with TB progression and poor treatment outcome in humans
Summary
Tuberculosis (TB), a chronic bacterial disease caused by Mycobacterium tuberculosis (Mtb), remains a major global health problem that claims 1.4 million lives annually. Genetic association studies commonly identify single nucleotide polymorphisms (SNPs) in pro-inflammatory innate immune mediators that are associated with TB susceptibility and regulate cellular function, such as TLRs, LTA4H, IL22, and IL6 [5,6,7,8,9,10]. These associations suggest that disease progression may be determined at multiple levels in human populations and that the inflammatory response could play a decisive role
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