Replicative Acinetobacter baumannii strains interfere with phagosomal maturation by modulating the vacuolar pH.

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 AcinetobacterContaining 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 alveolar 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. Author summary: Acinetobacter baumannii is an important nosocomial pathogen with the highest rate of multi-drug resistance among Gram negative bacteria. Although A. baumannii is capable to cause multiple types of infection, pneumonia is the main manifestation of this pathogen. We have recently shown that recent A. baumannii clinical isolates are able to multiply and persist in macrophages in vitro. Here we show that in a murine respiratory infection model, A. baumannii can also create niches within resident macrophages of the lung. Furthermore, we demonstrate that A. baumannii manipulates the macrophage endocytic pathway to create a replicative niche. Recent clinical isolates can withstand the acidic environment on the vacuole and neutralize it by secreting ammonia to the vacuolar lumen, which allows A. baumannii to further multiply inside the macrophage. The ability to survive and multiply within macrophages could be important to avoid the host immune system, avoid clearance, and withstand antibiotic treatment as many antibiotics cannot penetrate host cells. [ABSTRACT FROM AUTHOR]