Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism.
The progression of human tuberculosis (TB) to active disease and transmission involves the development of a caseous granuloma that cavitates and releases infectious Mycobacterium tuberculosis bacilli. In the current study, we exploited genome-wide microarray analysis to determine that genes for lipid sequestration and metabolism were highly expressed in caseous TB granulomas. Immunohistological analysis of these granulomas confirmed the disproportionate abundance of the proteins involved in lipid metabolism in cells surrounding the caseum; namely, adipophilin, acyl-CoA synthetase long-chain family member 1 and saposin C. Biochemical analysis of the lipid species within the caseum identified cholesterol, cholesteryl esters, triacylglycerols and lactosylceramide, which implicated low-density lipoprotein-derived lipids as the most likely source. M. tuberculosis infection in vitro induced lipid droplet formation in murine and human macrophages. Furthermore, the M. tuberculosis cell wall lipid, trehalose dimycolate, induced a strong granulomatous response in mice, which was accompanied by foam cell formation. These results provide molecular and biochemical evidence that the development of the human TB granuloma to caseation correlates with pathogen-mediated dysregulation of host lipid metabolism.
Kim
Mi-Jeong
MJ
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Wainwright
Helen C
HC
Locketz
Michael
M
Bekker
Linda-Gail
LG
Walther
Gabriele B
GB
Dittrich
Corneli
C
Visser
Annalie
A
Wang
Wei
W
Hsu
Fong-Fu
FF
Wiehart
Ursula
U
Tsenova
Liana
L
Kaplan
Gilla
G
Russell
David G
DG
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002364:Caseins; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000378:metabolism; D003311:Cord Factors / Q000633:toxicity; D053263:Gene Regulatory Networks; D006099:Granuloma / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007790:Lactosylceramides / Q000378:metabolism; D050356:Lipid Metabolism; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009336:Necrosis; D010455:Peptides / Q000378:metabolism; D000070780:Perilipin-2; D049231:Saposins / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014376:Tuberculosis / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D015703:Antigens, CD; D002364:Caseins; D002788:Cholesterol Esters; D003311:Cord Factors; D007790:Lactosylceramides; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D010455:Peptides; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D049231:Saposins; D014280:Triglycerides; C009744:CDw17 antigen; D002784:Cholesterol; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase