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Replicative Acinetobacter baumannii strains interfere with phagosomal maturation by modulating the vacuolar pH
Jesus S Distel1, Gisela Di Venanzio1, Joseph J Mackel2
1Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
Abstract:
Bacterial pneumonia is a common infection of the lower respiratory tract that can afflict patients of all ages. Multidrug-resistant strains of Acinetobacter baumannii are increasingly responsible for causing nosocomial pneumonias, thus posing an urgent threat. Alveolar macrophages play a critical role in overcoming respiratory infections caused by this pathogen. Recently, we and others have shown that new clinical isolates of A. baumannii, but not the common lab strain ATCC 19606 (19606), can persist and replicate in macrophages within spacious vacuoles that we called Acinetobacter Containing Vacuoles (ACV). In this work, we demonstrate that the modern A. baumannii clinical isolate 398, but not the lab strain 19606, can infect alveolar macrophages and produce ACVs in vivo in a murine pneumonia model. Both strains initially interact with the macrophage endocytic pathway, as indicated by EEA1 and LAMP1 markers; however, the fate of these strains diverges at a later stage. While 19606 is eliminated in an autophagy pathway, 398 replicates in ACVs and are not degraded. We show that 398 reverts the natural acidification of the phagosome by secreting large amounts of ammonia, a by-product of amino acid catabolism. We propose that this ability to survive within macrophages may be critical for the persistence of clinical A. baumannii isolates in the lung during a respiratory infection.
Insights
Clinical Acinetobacter baumannii isolates, unlike lab strains, can survive within lung macrophages by preventing phagosome acidification with ammonia. This macrophage survival mechanism may explain their persistence during pneumonia.
Area of Science:
- Immunology
- Microbiology
- Pathogenesis
Background:
- Multidrug-resistant Acinetobacter baumannii causes dangerous nosocomial pneumonias.
- Alveolar macrophages are crucial for fighting respiratory infections.
- Clinical A. baumannii strains, not lab strains, persist in macrophages within Acinetobacter Containing Vacuoles (ACV).
Purpose of the Study:
- To investigate the in vivo survival of a clinical A. baumannii isolate (398) versus a lab strain (19606) in alveolar macrophages during pneumonia.
- To elucidate the mechanisms by which A. baumannii persists within macrophages.
Main Methods:
- Infection of alveolar macrophages with A. baumannii strains 398 and 19606 in a murine pneumonia model.
- Analysis of bacterial fate within macrophages using endocytic pathway markers (EEA1, LAMP1) and autophagy.
- Measurement of phagosome acidification and ammonia secretion by A. baumannii.
Main Results:
- Clinical isolate 398, but not lab strain 19606, infected alveolar macrophages and formed ACVs in vivo.
- Strain 19606 was degraded via autophagy, while strain 398 replicated within ACVs.
- Strain 398 prevented phagosome acidification by secreting ammonia, a byproduct of amino acid catabolism.
Conclusions:
- Clinical A. baumannii isolates possess a unique mechanism to survive within alveolar macrophages.
- Ammonia secretion allows A. baumannii to evade phagosome acidification and degradation.
- Macrophage survival is a critical factor for the lung persistence of clinical A. baumannii strains in pneumonia.
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