WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis
Julius Brandenburg, Sebastian Marwitz, Simone C. Tazoll, Franziska Waldow, Barbara Kalsdorf, Tim Vierbuchen, Thomas Scholzen, Annette Gross, Svenja Goldenbaum, Alexandra Hölscher, Martina Hein, Lara Linnemann, Maja Reimann, Andreas Kispert, Michael Leitges, Jan Rupp, Christoph Lange, Stefan Niemann, Jochen Behrends, Torsten Goldmann, Holger Heine, Ulrich E. Schaible, Christoph Hölscher, Dominik Schwudke, Norbert Reiling
Julius Brandenburg, Sebastian Marwitz, Simone C. Tazoll, Franziska Waldow, Barbara Kalsdorf, Tim Vierbuchen, Thomas Scholzen, Annette Gross, Svenja Goldenbaum, Alexandra Hölscher, Martina Hein, Lara Linnemann, Maja Reimann, Andreas Kispert, Michael Leitges, Jan Rupp, Christoph Lange, Stefan Niemann, Jochen Behrends, Torsten Goldmann, Holger Heine, Ulrich E. Schaible, Christoph Hölscher, Dominik Schwudke, Norbert Reiling
View: Text | PDF
Research Article Infectious disease Metabolism

WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis

Abstract

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.

Authors

Julius Brandenburg, Sebastian Marwitz, Simone C. Tazoll, Franziska Waldow, Barbara Kalsdorf, Tim Vierbuchen, Thomas Scholzen, Annette Gross, Svenja Goldenbaum, Alexandra Hölscher, Martina Hein, Lara Linnemann, Maja Reimann, Andreas Kispert, Michael Leitges, Jan Rupp, Christoph Lange, Stefan Niemann, Jochen Behrends, Torsten Goldmann, Holger Heine, Ulrich E. Schaible, Christoph Hölscher, Dominik Schwudke, Norbert Reiling

×

Figure 5

The role of ACC2 during Mtb infection in vivo.

Options: View larger image (or click on image) Download as PowerPoint
The role of ACC2 during Mtb infection in vivo. (A and B) Immunohistochem...
(A and B) Immunohistochemical stainings for ACC2 (A) and the macrophage/monocyte marker CD68 (B) of consecutive lung tissue sections derived from a TB patient. A representative observation from 2 independent observations is shown. Results of these stainings are again shown in Supplemental Figure 8A. (C–L) In vivo effect of adjuvant ACC2 inhibitor treatment on Mtb infection in TB-susceptible mice. After 28 days of infection with Mtb (~200 CFUs), 129/Sv mice either were left untreated (pretreatment, d 28 p.i., n = 4, white symbols) or were treated for 14 days with INH alone (10 mg/kg body weight, n = 8, gray symbols) or with ACC2 inhibitor 3 (ND-646, 25 mg/kg body weight) plus INH (n = 10, red symbols). Lung weights (C), lung cytokine and chemokine levels (D–F), TAG and CE abundance in the lung (G), and mycobacterial loads in lung, spleen, and liver (H) were determined. (I–K) Mononuclear infiltrates in the livers of Mtb-infected mice (I, black arrows), and quantification of infiltrate numbers (J), infiltrate size (K), and the average CFUs per infiltrate (L). Statistical analyses were carried out using a 1-tailed, unpaired Student’s t test; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. Data are depicted as scatter dot plots with line at mean. Scale bars: 100 μm.