title: Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule.
abstract: Mycobacterium tuberculosis (Mtb) infection remains a global health crisis. Recent genetic evidence implicates specific cell envelope lipids in Mtb pathogenesis, but it is unclear whether these cell envelope compounds affect pathogenesis through a structural role in the cell wall or as pathogenesis effectors that interact directly with host cells. Here we show that cyclopropane modification of the Mtb cell envelope glycolipid trehalose dimycolate (TDM) is critical for Mtb growth during the first week of infection in mice. In addition, TDM modification by the cyclopropane synthase pcaA was both necessary and sufficient for proinflammatory activation of macrophages during early infection. Purified TDM isolated from a cyclopropane-deficient pcaA mutant was hypoinflammatory for macrophages and induced less severe granulomatous inflammation in mice, demonstrating that the fine structure of this glycolipid was critical to its proinflammatory activity. These results established the fine structure of lipids contained in the Mtb cell envelope as direct effectors of pathogenesis and identified temporal control of host immune activation through cyclopropane modification of TDM as a critical pathogenic strategy of Mtb.
authors.affiliation: Division of Infectious Diseases, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
authors.forename: Nagatoshi
authors.initials: N
authors.lastname: Fujiwara
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Michael S
authors.initials: MS
authors.lastname: Glickman
mesh_terms: D000818:Animals; D002460:Cell Line; D015169:Colony Count, Microbial; D003311:Cord Factors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D003521:Cyclopropanes / Q000737:chemistry; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000096:biosynthesis; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000235:genetics / Q000472:pathogenicity*; D014397:Tuberculosis, Pulmonary / Q000209:etiology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics
chemical_list: D003311:Cord Factors; D003521:Cyclopropanes; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C030797:cyclopropane; D008780:Methyltransferases; C019964:cyclopropane synthetase