A deletion defining a common Asian lineage ofMycobacterium tuberculosisassociates with immune subversion

• DOI: 10.1073/pnas.0604283103
• Publication Date: 2006-10-06T20:37:37Z
• Authors: Sandra M. Newton; Rebecca J. Smith; Katalin A. Wilkinson; Mark P. Nicol; Natalie J. Garton; Karl J. Staples; Graham R. Stewart; John R. Wain; Adrian R. Martineau; Sarah Fandrich; Timothy Smallie; Brian Foxwell; Ahmed Al-Obaidi; Jamila Shafi; Kumar Rajakumar; Beate Kampmann; Peter W. Andrew; Loems Ziegler-Hei...; Michael R. Barer; Robert J. Wilkinson
• Keywords: 0301 basic medicine; Phagocytes; Asia; Polymorphism, Genetic; Macrophages; 610; Mycobacterium tuberculosis; Monocytes; United Kingdom; 3. Good health; 03 medical and health sciences; Phenotype; Bacterial Proteins; Immune System; 616; Mutation; Disease Transmission, Infectious; Ethnicity; Cytokines; Humans; Tuberculosis; Cells, Cultured

Six major lineages ofMycobacterium tuberculosisappear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affectingRv1519in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H2O2-tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation ofRv1519, but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. TheRv1519polymorphism inM. tuberculosisconfers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.