Nutrient generation and retrieval from the host cell cytosol by intra-vacuolar Legionella pneumophila

Price, Christopher; Richards, Ashley M.; Kwaik, Yousef Abu

doi:10.3389/fcimb.2014.00111

Cited by 16 publications

(16 citation statements)

References 34 publications

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“…Importantly, the host cell death brought by MTOR inhibition required bacterial replication and was rescued when lipids were provided exogenously through serum or purified LDL particles further supporting the idea that MTOR activity regulates the lipid supply/demand ratio during the process of LCV expansion. Serum-derived lipids did not promote growth in axenic cultures nor in the early phase of intracellular replication, which supports a role for host-derived lipids in LCV biogenesis rather than bacterial replication and is consistent with the well documented Legionella utilization of carbohydrates and amino acids as biosynthesis and energy sources [3,79,80]. …”

Section: Discussionsupporting

confidence: 81%

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

et al. 2016

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Vacuolar bacterial pathogens are sheltered within unique membrane-bound organelles that expand over time to support bacterial replication. These compartments sequester bacterial molecules away from host cytosolic immunosurveillance pathways that induce antimicrobial responses. The mechanisms by which the human pulmonary pathogen Legionella pneumophila maintains niche homeostasis are poorly understood. We uncovered that the Legionella-containing vacuole (LCV) required a sustained supply of host lipids during expansion. Lipids shortage resulted in LCV rupture and initiation of a host cell death response, whereas excess of host lipids increased LCVs size and housing capacity. We found that lipids uptake from serum and de novo lipogenesis are distinct redundant supply mechanisms for membrane biogenesis in Legionella-infected macrophages. During infection, the metabolic checkpoint kinase Mechanistic Target of Rapamycin (MTOR) controlled lipogenesis through the Serum Response Element Binding Protein 1 and 2 (SREBP1/2) transcription factors. In Legionella-infected macrophages a host-driven response that required the Toll-like receptors (TLRs) adaptor protein Myeloid differentiation primary response gene 88 (Myd88) dampened MTOR signaling which in turn destabilized LCVs under serum starvation. Inactivation of the host MTOR-suppression pathway revealed that L. pneumophila sustained MTOR signaling throughout its intracellular infection cycle by a process that required the upstream regulator Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and one or more Dot/Icm effector proteins. Legionella-sustained MTOR signaling facilitated LCV expansion and inhibition of the PI3K-MTOR-SREPB1/2 axis through pharmacological or genetic interference or by activation of the host MTOR-suppression response destabilized expanding LCVs, which in turn triggered cell death of infected macrophages. Our work identified a host metabolic requirement for LCV homeostasis and demonstrated that L. pneumophila has evolved to manipulate MTOR-dependent lipogenesis for optimal intracellular replication.

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Section: Discussionsupporting

confidence: 81%

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

et al. 2016

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“…However, there was very little information available on the growth requirements of B. pseudomallei inside human macrophages. Most studies of the nutritional requirements of intracellular pathogens growing inside host cells have been performed on Legionella pneumophila (47,48), which can grow and replicate similarly in human macrophages and amoebae (49). Growing in both human macrophages and amoebae, L. pneumophila utilizes amino acids as its main sources of carbon, nitrogen and energy; L. pneumophila obtains amino acids from the host through proteasomal degradation (48).…”

Section: Flux Balance Analysismentioning

confidence: 99%

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

Challacombe

2015

Preprint

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“…Within the LCV, bacterial metabolism and nutrition-based genetic regulation based in nutrient availability governs bacterial proliferation and differentiation (W. Eisenreich, Heesemann, Rudel, & Goebel, 2013; Wolfgang Eisenreich, Rudel, Heesemann, & Goebel, 2017; Fonseca & Swanson, 2014; Grubmuller, Schauer, Goebel, Fuchs, & Eisenreich, 2014; Häuslein et al, 2017; Lama, Drennan, Johnson, Rubenstein, & Cambronne, 2017; Manske & Hilbi, 2014; Oliva, Sahr, & Buchrieser, 2018; C. T. Price, Richards, & Abu Kwaik, 2014).…”

mentioning

confidence: 99%

Evasion of phagotrophic predation by protist hosts and innate immunity of metazoan hosts byLegionella pneumophila

Best

Kwaik

2018

Cellular Microbiology

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Summary Legionella pneumophila is a ubiquitous environmental bacterium that has evolved to infect and proliferate within amoebae and other protists. It is thought that accidental inhalation of contaminated water particles by humans is what has enabled this pathogen to proliferate within alveolar macrophages and cause pneumonia. However, the highly evolved macrophages are equipped more sophisticated innate defense mechanisms than protists, such as the evolution of phagotrophic feeding into phagocytosis with more evolved innate defense processes. Not surprisingly, the majority of proteins involved in phagosome biogenesis (~80%) have origins in the phagotrophy stage of evolution. There are a plethora of highly evolved cellular and innate metazoan processes, not represented in Protist biology, that are modulated by L. pneumophila; including TLR2 signaling, NF-κB, apoptotic and inflammatory processes, histone modification, caspases, and the NLRC-Naip5 inflammasomes. Importantly, L. pneumophila infects hemocytes of the invertebrate Galleria mellonella, kill G. mellonella larvae, and proliferate in and kill Drosophila adult flies and Caenorhabditis elegans. Although co-evolution with protist hosts has provided a substantial blueprint for L. pneumophila to infect macrophages, we discuss the further evolutionary aspects of co-evolution of L. pneumophila and its adaptation to modulate various highly evolved innate metazoan processes prior to becoming a human pathogen.

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Nutrient generation and retrieval from the host cell cytosol by intra-vacuolar Legionella pneumophila

Cited by 16 publications

References 34 publications

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

Evasion of phagotrophic predation by protist hosts and innate immunity of metazoan hosts byLegionella pneumophila

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