On the killing of mycobacteria by macrophages

Molecular Pathogenesis Centre, Unit of Retrovirus and Associated Infections, Faculty of Pharmacy, University of Lisbon, Av. Forcas Armadas, 1600-083 Lisbon, Portugal.
Cellular Microbiology (Impact Factor: 4.92). 03/2008; 10(2):529-48. DOI: 10.1111/j.1462-5822.2007.01067.x
Source: PubMed


Both pathogenic and non-pathogenic mycobacteria are internalized into macrophage phagosomes. Whereas the non-pathogenic types are invariably killed by all macrophages, the pathogens generally survive and grow. Here, we addressed the survival, production of nitrogen intermediates (RNI) and intracellular trafficking of the non-pathogenic Mycobacterium smegmatis, the pathogen-like, BCG and the pathogenic M. bovis in different mouse, human and bovine macrophages. The bacteriocidal effects of RNI were restricted for all bacterial species to the early stages of infection. EM analysis showed clearly that all the mycobacteria remained within phagosomes even at late times of infection. The fraction of BCG and M. bovis found in mature phagolysosomes rarely exceeded 10% of total, irrespective of whether bacteria were growing, latent or being killed, with little correlation between the extent of phagosome maturation and the degree of killing. Theoretical modelling of our data identified two different potential sets of explanations that are consistent with our results. The model we favour is one in which a small but significant fraction of BCG is killed in an early phagosome, then maturation of a small fraction of phagosomes with both live and killed bacteria, followed by extremely rapid killing and digestion of the bacteria in phago-lysosomes.

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Available from: Luisa Jordao,
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    • "In addition, actin filament assembly also plays a role in the pro-inflammatory response. Several signaling lipids, cAMP, extracellular ATP and the P2X7 receptor, were shown to be involved in actin assembly and the killing/survival of pathogenic mycobacteria (Kalamidas et al., 2006; Treede et al., 2007; Jordao et al., 2008a,b; Kühnel et al., 2008; Kuehnel et al., 2009). Furthermore, some lipid effectors that regulate actin assembly also control NF-κB, a transcription factor involved in the pro-inflammatory response (Gutierrez et al., 2009). "
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    • "In contrast, monocytes from human peripheral blood did not to release DNA when stimulated in a fashion that normally evokes NET formation in neutrophils (Fuchs et al., 2007). Whereas neutrophils are indispensible in the defense against most extracellular bacteria, the monocyte/macrophage lineage is vital in eliminating bacteria with capacity to persist inside phagocytes, for example, mycobacteria (van der Wel et al., 2007; Jordao et al., 2008). "
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    • "resides largely within a phagosome-like compartment of host macrophages during infection (Jordao et al., 2008). Inflammasome activation it is postulated to occur only if these effectors or products from a signalling cascade reach the cytosol and gain access to NLRs. "

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