TY - JOUR
T1 - WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis
AU - Brandenburg, Julius
AU - Marwitz, Sebastian
AU - Tazoll, Simone C.
AU - Waldow, Franziska
AU - Kalsdorf, Barbara
AU - Vierbuchen, Tim
AU - Scholzen, Thomas
AU - Gross, Annette
AU - Goldenbaum, Svenja
AU - Hölscher, Alexandra
AU - Hein, Martina
AU - Linnemann, Lara
AU - Reimann, Maja
AU - Kispert, Andreas
AU - Leitges, Michael
AU - Rupp, Jan
AU - Lange, Christoph
AU - Niemann, Stefan
AU - Behrends, Jochen
AU - Goldmann, Torsten
AU - Heine, Holger
AU - Schaible, Ulrich E.
AU - Hölscher, Christoph
AU - Schwudke, Dominik
AU - Reiling, Norbert
N1 - Publisher Copyright:
Copyright: © 2021, American Society for Clinical Investigation.
PY - 2021/8/16
Y1 - 2021/8/16
N2 - In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden “foamy” macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/ Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.
AB - In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden “foamy” macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/ Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.
UR - http://www.scopus.com/inward/record.url?scp=85113140874&partnerID=8YFLogxK
U2 - 10.1172/JCI141833
DO - 10.1172/JCI141833
M3 - Journal articles
C2 - 34255743
AN - SCOPUS:85113140874
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 16
M1 - e141833
ER -