TY - JOUR
T1 - Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism
AU - Kim, Mi Jeong
AU - Wainwright, Helen C.
AU - Locketz, Michael
AU - Bekker, Linda Gail
AU - Walther, Gabriele B.
AU - Dittrich, Corneli
AU - Visser, Annalie
AU - Wang, Wei
AU - Hsu, Fong Fu
AU - Wiehart, Ursula
AU - Tsenova, Liana
AU - Kaplan, Gilla
AU - Russell, David G.
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
KW - Foamy macrophage
KW - Granuloma
KW - Mycobacterium
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=77956930778&partnerID=8YFLogxK
U2 - 10.1002/emmm.201000079
DO - 10.1002/emmm.201000079
M3 - Article
C2 - 20597103
AN - SCOPUS:77956930778
SN - 1757-4676
VL - 2
SP - 258
EP - 274
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
ER -