Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells
- KwaZulu-Natal Research Institute for TB-HIV, South Africa
Abstract
A hallmark of pulmonary tuberculosis is formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states.
Article and author information
Author details
Funding
Bill and Melinda Gates Foundation (OPP1116944)
- Alex Sigal
Human Frontier Science Program (CDA00050/2013-C)
- Alex Sigal
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Larry Schlesinger
Ethics
Human subjects: Blood was obtained from adult healthy volunteers after written informed consent (University of KwaZulu-Natal Institutional Review Board approval BE022/13). Alveolar macrophages were obtained from bronchoalveolar lavage as part of an indicated diagnostic procedure after written informed consent (University of KwaZulu-Natal Institutional Review Board approval BE037/12).
Version history
- Received: October 1, 2016
- Accepted: January 27, 2017
- Accepted Manuscript published: January 28, 2017 (version 1)
- Version of Record published: February 21, 2017 (version 2)
- Version of Record updated: May 5, 2017 (version 3)
Copyright
© 2017, Mahamed et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells
eLife 6:e22028.
https://doi.org/10.7554/eLife.22028
Further reading
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- Computational and Systems Biology
Transcriptomic profiling became a standard approach to quantify a cell state, which led to accumulation of huge amount of public gene expression datasets. However, both reuse of these datasets or analysis of newly generated ones requires significant technical expertise. Here we present Phantasus - a user-friendly web-application for interactive gene expression analysis which provides a streamlined access to more than 96000 public gene expression datasets, as well as allows analysis of user-uploaded datasets. Phantasus integrates an intuitive and highly interactive JavaScript-based heatmap interface with an ability to run sophisticated R-based analysis methods. Overall Phantasus allows users to go all the way from loading, normalizing and filtering data to doing differential gene expression and downstream analysis. Phantasus can be accessed on-line at https://alserglab.wustl.edu/phantasus or can be installed locally from Bioconductor (https://bioconductor.org/packages/phantasus). Phantasus source code is available at https://github.com/ctlab/phantasus under MIT license.
