Brucella Genital Tropism: What's on the Menu

Letesson, Jean‐Jacques; Barbier, Thibault; Zúñiga-Ripa, Amaia; Godfroid, Jacques; Bolle, Xavier De; Moriyón, Ignacio

doi:10.3389/fmicb.2017.00506

Cited by 26 publications

(34 citation statements)

References 49 publications

(51 reference statements)

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“…Brucella species pathogens have a tropism for genital organs, and the possibility that lactate serves as an important metabolic substrate for Brucella spp. during colonization of the reproductive tract has been recently reviewed by Letesson and colleagues (33).…”

Section: Discussionmentioning

confidence: 99%

“…While classically activated M1 macrophages undergo a shift to Warburg-like metabolism upon exposure to pathogen-associated molecular patterns (PAMPs), Xavier and colleagues have shown that B. abortus preferentially infects alternatively activated M2 macrophages in mice, which have an opposite metabolic profile, showing decreased aerobic glycolysis (12). As recently noted (26,33), the physiological characteristics of host cell types and tissues colonized by Brucella spp. during the course of disease vary significantly, and it may be that lactate catabolism is important in some in vivo microenvironments but irrelevant in others.…”

Section: Discussionmentioning

confidence: 99%

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Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen

2017

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Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected with Brucella abortus undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well described in cancer cells and also occurs in activated inflammatory cells. B. abortus efficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect in vitro growth of B. abortus in axenic culture but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and B. abortus uses this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens.IMPORTANCE Brucella spp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with Brucella abortus undergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism inhibit intracellular replication and decrease the survival of B. abortus in an in vitro infection model; these drugs may be broadly useful therapeutics for intracellular infections.KEYWORDS infection, Warburg effect, lactate, therapeutics, antimetabolite drug, 3-bromopyruvic acid, NHI-2, 2-deoxy-D-glucose, brucellosis, antibiotic, metabolism, zoonotic infection M acrophages can be activated by pathogen-associated proinflammatory molecules, such as lipopolysaccharide (LPS). Classically activated (i.e., M1) macrophages undergo a major metabolic shift in which the tricarboxylic acid (TCA) cycle is downregulated, and energy production transitions from oxidative phosphorylation to the less efficient process of aerobic glycolysis (1, 2). This change in metabolism, known as the Warburg effect (3), is a well-described metabolic feature of cancer cells (4).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen

2017

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“…The reasons for the preferential colonization of reproductive organs by the brucellae are not fully understood, and they may involve nutritional, immune, and hormonal factors (Samartino and Enright, 1993; Letesson et al, 2017). One of the molecular bases that is proposed to account, at least partially, for this tropism is the existence of erythritol in the target organs of ungulates (Smith et al, 1962).…”

Section: Introductionmentioning

confidence: 99%

Erythritol Availability in Bovine, Murine and Human Models Highlights a Potential Role for the Host Aldose Reductase during Brucella Infection

et al. 2017

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Erythritol is the preferential carbon source for most brucellae, a group of facultative intracellular bacteria that cause a worldwide zoonosis. Since this polyol is abundant in genital organs of ruminants and swine, it is widely accepted that erythritol accounts at least in part for the characteristic genital tropism of brucellae. Nevertheless, proof of erythritol availability and essentiality during Brucella intracellular multiplication has remained elusive. To investigate this relationship, we compared ΔeryH (erythritol-sensitive and thus predicted to be attenuated if erythritol is present), ΔeryA (erythritol-tolerant but showing reduced growth if erythritol is a crucial nutrient) and wild type B. abortus in various infection models. This reporting system indicated that erythritol was available but not required for B. abortus multiplication in bovine trophoblasts. However, mice and humans have been considered to lack erythritol, and we found that it was available but not required for B. abortus multiplication in human and murine trophoblastic and macrophage-like cells, and in mouse spleen and conceptus (fetus, placenta and envelopes). Using this animal model, we found that B. abortus infected cells and tissues contained aldose reductase, an enzyme that can account for the production of erythritol from pentose cycle precursors.

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“…pathogens have a tropism for genital organs, and the possibility that lactate may serve as an important metabolic substrate for Brucella spp. during colonization of the reproductive tract has been recently reviewed by Letesson and colleagues (33).…”

Section: Discussionmentioning

confidence: 99%

Brucella abortusinduces a Warburg shift in host metabolism that is linked to enhanced intracellular survival of the pathogen

Czyż

Willett

Crosson

2017

Preprint

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Brucella abortus induces a Warburg shift in host metabolism that is linked toHoward Taylor Ricketts Laboratory, University of Chicago, Argonne National that is well-described in cancer cells, and also occurs in activated inflammatory cells. B. 5abortus efficiently uses lactic acid as its sole carbon and energy source and requires the 2 6 ability to metabolize lactate for normal survival in human macrophage-like cells. We 25, 2017; 3 host cells produce lactic acid and have reduced amino acid catabolism. We provide defenses by increasing concentrations of ROS and reactive nitrogen intermediates (6). response to support infection. 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/120527 doi: bioRxiv preprint first posted online Mar.4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http:/ RESULTS 2Brucella abortus infection of human macrophage-like cells disrupts mitochondrial To characterize the effect of intracellular colonization by B. abortus on human were cultivated in minimal essential medium in the presence of central metabolic substrates specifically selected to measure mitochondrial function.

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Brucella Genital Tropism: What's on the Menu

Cited by 26 publications

References 49 publications

Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen

Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen

Erythritol Availability in Bovine, Murine and Human Models Highlights a Potential Role for the Host Aldose Reductase during Brucella Infection

Brucella abortusinduces a Warburg shift in host metabolism that is linked to enhanced intracellular survival of the pathogen

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