Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis

Mary Speir, Kate E. Lawlor, Stefan P. Glaser, Gilu Abraham, Seong Chow, Adam Vogrin, Keith E. Schulze, Ralf Schuelein, Lorraine A. O'Reilly, Kylie Mason, Elizabeth L. Hartland, Trevor Lithgow, Andreas Strasser, Guillaume Lessene, David C. S. Huang, James E. Vince, Thomas Naderer

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease 1. Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.

Original languageEnglish
Article number15034
Number of pages9
JournalNature Microbiology
Volume1
Issue number3
DOIs
Publication statusPublished - 24 Feb 2016

Keywords

  • apoptosis
  • bacterial pathogenesis
  • immune cell death
  • pathogens

Cite this

Speir, Mary ; Lawlor, Kate E. ; Glaser, Stefan P. ; Abraham, Gilu ; Chow, Seong ; Vogrin, Adam ; Schulze, Keith E. ; Schuelein, Ralf ; O'Reilly, Lorraine A. ; Mason, Kylie ; Hartland, Elizabeth L. ; Lithgow, Trevor ; Strasser, Andreas ; Lessene, Guillaume ; Huang, David C. S. ; Vince, James E. ; Naderer, Thomas. / Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis. In: Nature Microbiology. 2016 ; Vol. 1, No. 3.
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abstract = "Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease 1. Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.",
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Speir, M, Lawlor, KE, Glaser, SP, Abraham, G, Chow, S, Vogrin, A, Schulze, KE, Schuelein, R, O'Reilly, LA, Mason, K, Hartland, EL, Lithgow, T, Strasser, A, Lessene, G, Huang, DCS, Vince, JE & Naderer, T 2016, 'Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis', Nature Microbiology, vol. 1, no. 3, 15034. https://doi.org/10.1038/nmicrobiol.2015.34

Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis. / Speir, Mary; Lawlor, Kate E.; Glaser, Stefan P.; Abraham, Gilu; Chow, Seong; Vogrin, Adam; Schulze, Keith E.; Schuelein, Ralf; O'Reilly, Lorraine A.; Mason, Kylie; Hartland, Elizabeth L.; Lithgow, Trevor ; Strasser, Andreas; Lessene, Guillaume; Huang, David C. S.; Vince, James E.; Naderer, Thomas.

In: Nature Microbiology, Vol. 1, No. 3, 15034, 24.02.2016.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Speir, Mary

AU - Lawlor, Kate E.

AU - Glaser, Stefan P.

AU - Abraham, Gilu

AU - Chow, Seong

AU - Vogrin, Adam

AU - Schulze, Keith E.

AU - Schuelein, Ralf

AU - O'Reilly, Lorraine A.

AU - Mason, Kylie

AU - Hartland, Elizabeth L.

AU - Lithgow, Trevor

AU - Strasser, Andreas

AU - Lessene, Guillaume

AU - Huang, David C. S.

AU - Vince, James E.

AU - Naderer, Thomas

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N2 - Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease 1. Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.

AB - Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease 1. Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.

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