Distel Jesus S, Di Venanzio Gisela, Mackel Joseph J, Rosen David A, Feldman Mario F
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
Department of Pediatrics, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO, United States.
bioRxiv. 2023 Feb 2:2023.02.02.526753. doi: 10.1101/2023.02.02.526753.
Bacterial pneumonia is a common infection of the lower respiratory tract that can afflict patients of all ages. Multidrug-resistant strains of 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 , but not the common lab strain ATCC 19606 (19606), can persist and replicate in macrophages within spacious vacuoles that we called C ontaining V acuoles (ACV). In this work, we demonstrate that the modern clinical isolate 398, but not the lab strain 19606, can infect alveolar macrophages and produce ACVs 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 isolates in the lung during a respiratory infection.
细菌性肺炎是一种常见的下呼吸道感染，可侵袭各年龄段的患者。多重耐药菌株越来越多地导致医院获得性肺炎，从而构成紧迫威胁。肺泡巨噬细胞在克服由这种病原体引起的呼吸道感染中起关键作用。最近，我们和其他人已经表明，新型临床分离株，而不是常见的实验室菌株ATCC 19606（19606），可以在我们称为含泡小体（ACV）的宽敞液泡内的巨噬细胞中持续存在并复制。在这项工作中，我们证明现代临床分离株398，而不是实验室菌株19606，可以在小鼠肺炎模型中感染肺泡巨噬细胞并产生ACV。两种菌株最初都与肺泡巨噬细胞内吞途径相互作用，如EEA1和LAMP1标记所示；然而，这些菌株的命运在后期出现分歧。虽然19606在自噬途径中被清除，但398在ACV中复制且不被降解。我们表明398通过分泌大量氨（氨基酸分解代谢的副产物）来逆转吞噬体的自然酸化。我们提出这种在巨噬细胞内存活的能力对于临床分离株在呼吸道感染期间在肺部的持续存在可能至关重要。
