Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern.
Mycolic acids (MAs) occur in the cell wall of Mycobacterium tuberculosis as variable mixtures of different classes and chain lengths. Here, we address the relationship between the structure and its inflammatory function of this virulence factor using single synthetic MA isomers, differing in oxygenation class and cis- versus α-methyl-trans proximal cyclopropane orientation. Analysis of bronchoalveolar inflammation, lung histopathology and alveolar macrophage transcription revealed a strong dependence on these meromycolic chemistries of mouse pulmonary inflammation in response to intratracheal treatments with MAs. Whereas α-MA was inert, oxygenated methoxy- and keto-MA with cis-cyclopropane stereochemistry elicited solid to mild inflammatory responses respectively. In trans-cyclopropane orientation, methoxy-MA partially lost its inflammatory activity and keto-MA exerted anti-inflammatory alternative activation of alveolar macrophages and counteracted cis-methoxy-MA induced airway inflammation. The differential innate immune activities of MAs demonstrated here, dependent on oxygenation class and cis versus α-methyl-trans cyclopropane chemistry, identify a novel means for M. tuberculosis to steer host immune responses during infection.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Seppe
S
Vander Beken
Juma'a R
JR
Al Dulayymi
Thomas
T
Naessens
Gani
G
Koza
Max
M
Maza-Iglesias
Richard
R
Rowles
Cornelia
C
Theunissen
Jelle
J
De Medts
Ellen
E
Lanckacker
Mark S
MS
Baird
Johan
J
Grooten
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D005260:Female; D015870:Gene Expression / Q000235:genetics; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D008081:Liposomes; D008168:Lung / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000276:immunology; D009171:Mycolic Acids / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology* / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D013237:Stereoisomerism; D037521:Virulence Factors / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology* / Q000494:pharmacology
D008081:Liposomes; D009171:Mycolic Acids; D037521:Virulence Factors; C013596:meromycolic acids