Cellular cholesterol licenses Legionella pneumophila intracellular replication in macrophages
Authors:Edna Ondari1,#, Ashley Wilkins1,#, Brian Latimer3, Ana-Maria Dragoi2,3 and Stanimir S. Ivanov1
doi: 10.15698/mic2023.01.789
Volume 10, pp. 1 to 17, published 06/12/2022.
1 Department of Microbiology and Immunology, Louisiana State University Health – Shreveport, Shreveport, LA 71130.
2 Department of Molecular and Cellular Physiology, Louisiana State University Health – Shreveport, Shreveport, LA 71130.
3 Innovative North Louisiana Experimental Therapeutics program (INLET), Feist-Weiller Cancer Center, Louisiana State University Health – Shreveport, Shreveport, LA 71130.
# Equal contribution.
Keywords:
Legionella pneumophila, macrophage, intracellular replication, cholesterol, niche homeostasis.
Corresponding Author(s):
Conflict of interest statement:
The authors declare that no competing interests exist.
Please cite this article as:
Edna Ondari, Ashley Wilkins, Brian Latimer, Ana-Maria Dragoi and Stanimir S. Ivanov (2022). Cellular cholesterol licenses Legionella pneumophila intracellular replication in mac-rophages. Microbial Cell 10(1): 1-17. doi: 10.15698/mic2023.01.789
© 2022 Ondari et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
Host membranes are inherently critical for niche homeostasis of vacuolar pathogens. Thus, intracellular bacteria frequently encode the capacity to regulate host lipogenesis as well as to modulate the lipid composition of host membranes. One membrane component that is often subverted by vacuolar bacteria is cholesterol – an abundant lipid that mammalian cells produce de novo at the endoplasmic reticulum (ER) or acquire exogenously from serum-derived lipoprotein carriers. Legionella pneumophila is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires’ disease. From within a unique ER-derived vacuole L. pneumophila promotes host lipogenesis and experimental evidence indicates that cholesterol production might be one facet of this response. Here we investigated the link between cellular cholesterol and L. pneumophila intracellular replication and discovered that disruption of cholesterol biosynthesis or cholesterol trafficking lowered bacterial replication in infected cells. These growth defects were rescued by addition of exogenous cholesterol. Conversely, bacterial growth within cholesterol-leaden macrophages was enhanced. Importantly, the growth benefit of cholesterol was observed strictly in cellular infections and L. pneumophila growth kinetics in axenic cultures did not change in the presence of cholesterol. Microscopy analyses indicate that cholesterol regulates a step in L. pneumophila intracellular lifecycle that occurs after bacteria begin to replicate within an established intracellular niche. Collectively, we provide experimental evidence that cellular cholesterol promotes L. pneumophila replication within a membrane bound organelle in infected macrophages.