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.
- Alex Sigal
- Alex Sigal
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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).
- Larry Schlesinger
© 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.
The muscle synergy is a guiding concept in motor control research that relies on the general notion of muscles ‘working together’ towards task performance. However, although the synergy concept has provided valuable insights into motor coordination, muscle interactions have not been fully characterised with respect to task performance. Here, we address this research gap by proposing a novel perspective to the muscle synergy that assigns specific functional roles to muscle couplings by characterising their task-relevance. Our novel perspective provides nuance to the muscle synergy concept, demonstrating how muscular interactions can ‘work together’ in different ways: (1) irrespective of the task at hand but also (2) redundantly or (3) complementarily towards common task-goals. To establish this perspective, we leverage information- and network-theory and dimensionality reduction methods to include discrete and continuous task parameters directly during muscle synergy extraction. Specifically, we introduce co-information as a measure of the task-relevance of muscle interactions and use it to categorise such interactions as task-irrelevant (present across tasks), redundant (shared task information), or synergistic (different task information). To demonstrate these types of interactions in real data, we firstly apply the framework in a simple way, revealing its added functional and physiological relevance with respect to current approaches. We then apply the framework to large-scale datasets and extract generalizable and scale-invariant representations consisting of subnetworks of synchronised muscle couplings and distinct temporal patterns. The representations effectively capture the functional interplay between task end-goals and biomechanical affordances and the concurrent processing of functionally similar and complementary task information. The proposed framework unifies the capabilities of current approaches in capturing distinct motor features while providing novel insights and research opportunities through a nuanced perspective to the muscle synergy.