Eliminating infectious disease via BCL-2 inhibition

Eliminating infectious disease via BCL-2 inhibition

Partnering opportunity in infectious disease:

Eliminating infectious disease via BCL-2 inhibition

 

Team

Professor Marc Pellegrini, Dr James Vince, Dr Thomas Naderer

Background

Legionnaires’ disease is a form of atypical pneumonia caused by any type of Legionella bacteria. It is usually spread by breathing in contaminated water and/or soil. The bacteria replicate primarily within alveolar macrophages by using a type IV secretion system (T4SS).

The T4SS translocates more than 300 effector proteins into the host cell and is required for establishment of the replicative niche. However, the functional redundancy among many effectors has so far hampered the development of pathogen-targeted compounds that reduce Legionella virulence.

In addition, the mortality rate of infected individuals has remained at more than 10 per cent, despite state-of-the-art hospital care, suggesting that alternative treatment options to current front-line antibiotics are needed.

The technology

Rather than targeting bacterial pathways, our researchers have focused on host BCL-2 family members, which support Legionella growth by preventing macrophage apoptosis.

Using genetic deletion or pharmacological inhibition (with compounds co-developed at the Institute, ABT-199, ABT-737, ABT-263), we have shown 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 loss of BCL-XL, limits Legionella replication and prevents lethal lung infections in research models.

These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires’ disease and other diseases caused by intracellular microbes.

Applications

The incidence of Legionnaires’ disease is difficult to gauge due to different levels of surveillance and reporting across the globe. In Australia, Europe and the US it is estimated to infect 10-15 people per million, however this rate increases during an outbreak as hospitalisation and fatality rises dramatically.

BH3 mimetics may also be used to treat other types of bacterial infection including Mycobacterium, Salmonella, Staphylococcus, pathogenic E.coli and Pseudomonas.

Intellectual property

A PCT application has been filed that includes methods of using BH3 mimetics to treat an infection.

Opportunity for partnership

We are seeking a partner to co-invest in the development of negative regulators of host cell death signalling as drug targets in infectious diseases such as Legionnaires.

Key publication

  • Speir M. et al. 2016. Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis. Nat Microbiol. 2016 Feb 24;1:15034 PMID: 27572165

Contact

Dr Lauren Giorgio, Business Development Associate

Phone: +61 3 9345 2779 Email: giorgio.l@wehi.edu.au

 

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