Metabolic Adaptations of Intracellullar Bacterial Pathogens and their Mammalian Host Cells during Infection (“Pathometabolism”)

Eisenreich, Wolfgang; Heesemann, Jürgen; Rudel, Thomas; Goebel, Werner

doi:10.1128/microbiolspec.mbp-0002-2014

Cited by 46 publications

(36 citation statements)

References 207 publications

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“…The building blocks of intracellular niches harboring pathogens are host-derived, thus the metabolic state of the host cell frequently dictates replication permissiveness [1,69,70]. As a central metabolic regulator in eukaryotes, MTOR is frequently targeted by viruses for metabolic reprogramming [71].…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

et al. 2016

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“…These metabolic changes may in turn influence the metabolism of the intracellular bacteria. Thus, a complex network of metabolic interactions between the IBPs and host cells exists which determines the fate of IBPs within host cells, especially immune cells of the IIS (Eisenreich et al, 2015). …”

Section: Metabolic Characteristics Of Intracellular Bacterial Pathogementioning

confidence: 99%

“…These IBPs, but even the above mentioned metabolic generalists may pursue an intracellular metabolic strategy to achieve optimal intracellular replication which we recently termed “bipartite metabolism” (Grubmüller et al, 2014; Abu Kwaik and Bumann, 2015; Eisenreich et al, 2015). In this scenario, a combination of several host cell-derived carbon compounds drives the intracellular microbial metabolism and thereby allows a fine-tuned adaptation to the host cell (Figure 6).…”

Section: Metabolic Adaptations Of Iis Cells and The Ibpsmentioning

confidence: 99%

“…There is growing evidence that both, the efficient expression of the antimicrobial activities of the immune cells and the successful replication of IBPs within these cells require specific metabolic programs in both interacting partners for which the terms “immunometabolism” (Rathmell, 2012; Pollizzi and Powell, 2014) and “pathometabolism” (Eisenreich et al, 2015), respectively, have been coined. These two metabolic entities seem to mutually influence each other when the immune cells meet IBPs.…”

Section: Introductionmentioning

confidence: 99%

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To Eat and to Be Eaten: Mutual Metabolic Adaptations of Immune Cells and Intracellular Bacterial Pathogens upon Infection

Eisenreich

Rudel

Heesemann

et al. 2017

Front. Cell. Infect. Microbiol.

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Intracellular bacterial pathogens (IBPs) invade and replicate in different cell types including immune cells, in particular of the innate immune system (IIS) during infection in the acute phase. However, immune cells primarily function as essential players in the highly effective and integrated host defense systems comprising the IIS and the adaptive immune system (AIS), which cooperatively protect the host against invading microbes including IBPs. As countermeasures, the bacterial pathogens (and in particular the IBPs) have developed strategies to evade or reprogram the IIS at various steps. The intracellular replication capacity and the anti-immune defense responses of the IBP's as well as the specific antimicrobial responses of the immune cells of the innate and the AIS depend on specific metabolic programs of the IBPs and their host cells. The metabolic programs of the immune cells supporting or counteracting replication of the IBPs appear to be mutually exclusive. Indeed, recent studies show that upon interaction of naïve, metabolically quiescent immune cells with IBPs, different metabolic activation processes occur which may result in the provision of a survival and replication niche for the pathogen or its eradication. It is therefore likely that within a possible host cell population subsets exist that are metabolically programmed for pro- or anti-microbial conditions. These metabolic programs may be triggered by the interactions between different bacterial agonistic components and host cell receptors. In this review, we summarize the current status in the field and discuss metabolic adaptation processes within immune cells of the IIS and the IBPs that support or restrict the intracellular replication of the pathogens.

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“…Streptococcus pyogenes and Mtb both produce glycohydrolases that deplete nicotinamide adenine dinucleotide (NAD + ), a key metabolite in macrophage function (13, 14). Additionally, these metabolic switches are targeted by pathogens to re-program host cellular metabolism to meet their nutritional requirements (“pathometabolism”) (15). Leishmania infantum utilizes host cell SIRT-1 and AMPK energy sensors to switch cell metabolism from glycolysis to oxidative phosphorylation, a requirement for L. infantum survival (16).…”

Section: Precision Medicine—molecularly Targeted Therapies To Reversementioning

confidence: 99%

Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases

Mahon

Hafner

2017

Front. Immunol.

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To meet the challenges of increasing antimicrobial resistance, the infectious disease community needs innovative therapeutics. Precision medicine and immunotherapies are transforming cancer therapeutics by targeting the regulatory signaling pathways that are involved not only in malignancies but also in the metabolic and immunologic function of the tumor microenvironment. Infectious diseases target many of the same regulatory pathways as they modulate host metabolic functions for their own nutritional requirements and to impede host immunity. These similarities and the advances made in precision medicine and immuno-oncology that are relevant for the current development of host-directed therapies (HDTs) to treat infectious diseases are discussed. To harness this potential, improvements in drug screening methods and development of assays that utilize the research tools including high throughput multiplexes already developed by oncology are essential. A multidisciplinary approach that brings together immunologists, infectious disease specialists, and oncologists will be necessary to fully develop the potential of HDTs.

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Metabolic Adaptations of Intracellullar Bacterial Pathogens and their Mammalian Host Cells during Infection (“Pathometabolism”)

Cited by 46 publications

References 207 publications

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

To Eat and to Be Eaten: Mutual Metabolic Adaptations of Immune Cells and Intracellular Bacterial Pathogens upon Infection

Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases

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