Mitochondrial ROS potentiates indirect activation of the AIM2 inflammasome

Crane, Deborah D.; Bauler, Timothy J.; Wehrly, Tara D.; Bosio, Catharine M.

doi:10.3389/fmicb.2014.00438

Cited by 51 publications

(37 citation statements)

References 24 publications

(30 reference statements)

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“…Specifically, bacteria in which PE synthesis has been decreased have greater sensitivity to external stressors such as detergents and reactive oxygen species [30]. We previously demonstrated that F. novicida was significantly more sensitive to reactive oxygen species when it was compared to virulent Ftt [31]; this may be a result of differential ratios of phospholipids in their membranes. We are currently quantifying specific lipid species among strains of Francisella to determine if there are correlations with the relative virulence of each bacterium.…”

Section: Discussionmentioning

confidence: 99%

Unique Francisella Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid

Ireland¹,

Schwarz²,

Nardone³

et al. 2018

J Innate Immun

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Virulent Francisella tularensis subsp. tularensis (Ftt) is a dynamic, intracellular, bacterial pathogen. Its ability to evade and rapidly suppress host inflammatory responses is considered a key element for its profound virulence. We previously established that Ftt lipids play a role in inhibiting inflammation, but we did not determine the lipid species mediating this process. Here, we show that a unique, abundant, phosphatidylethanolamine (PE), present in Francisella, contributes to driving the suppression of inflammatory responses in human and mouse cells. Acyl chain lengths of this PE, C24: 0 and C10: 0, were key to the suppressive capabilities of Francisella PE. Addition of synthetic PE 24: 0–10: 0 resulted in the accumulation of PE in host cells for up to 24 h of incubation, and recapitulated the inhibition of inflammatory responses observed with native Ftt PE. Importantly, this novel PE significantly inhibited inflammatory responses driven by a medically and globally important flavivirus, dengue fever virus. Thus, targeting these lipids and/or the pathways that they manipulate represents a new strategy to combat immunosuppression engendered by Ftt, but they also show promise as a novel therapeutic intervention for significant viral infections.

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Section: Discussionmentioning

confidence: 99%

Unique Francisella Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid

Ireland¹,

Schwarz²,

Nardone³

et al. 2018

J Innate Immun

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“…Mitochondrial ROS (mROS) is an additional source of ROS in host cells which is increased during aerobic glycolysis (35). We have previously established that enhanced susceptibility of attenuated F. novicida to mROS contributes to the ability of these organisms to promote inflammatory responses in macrophages (36). However, inhibition of mROS also reverses aerobic glycolysis (35).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming of Host Cells by Virulent Francisella tularensis for Optimal Replication and Modulation of Inflammation

Wyatt

Diaz

Griffin

et al. 2016

The Journal of Immunology

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A shift in macrophage metabolism from oxidative phosphorylation to aerobic glycolysis is a requirement for activation to effectively combat invading pathogens. Francisella tularensis is a facultative intracellular bacterium that causes an acute, fatal disease called tularemia. Its primary mechanism of virulence is its ability to evade and suppress inflammatory responses while replicating in the cytosol of macrophages. The means by which F. tularensis modulates macrophage activation are not fully elucidated. Here we demonstrate that virulent F. tularensis impairs production of inflammatory cytokines in primary macrophages by preventing their shift to aerobic glycolysis, as evidenced by the down regulation of HIF-1α, and failure to upregulate pfkfb3. We also uncover that Francisella capsule is required for this process. In addition to modulating inflammatory responses, inhibition of glycolysis in host cells is also required for early replication of virulent Francisella. Together our data demonstrate that metabolic reprogramming of host cells by F. tularensis is a key component of both inhibition of host defense mechanisms and replication of the bacterium.

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“…The activation of the inflammasome is a crucial step for the clearance of many intracellular bacteria like Francisella novicida, Shigella flexneri, Legionella pneumophila, Listeria monocytogenes, and Salmonella typhimurium. 29 These ALRs directly bind with the cytoplasmic double-stranded DNA of the pathogen through their HIN-200 domain to form a large inflammasome complex. The completely assembled ALR inflammasome further recruits and subsequently oligomerizes ASC (Apoptosis-associated speck-like protein containing a CARD) which is a caspase-1-activating adaptor protein.…”

Section: Aim2 (Absent In Melanoma 2)-like Receptors (Alrs)mentioning

confidence: 99%

A tug-of-war between the host and the pathogen generates strategic hotspots for the development of novel therapeutic interventions against infectious diseases

et al. 2015

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Mitochondrial ROS potentiates indirect activation of the AIM2 inflammasome

Cited by 51 publications

References 24 publications

Unique <b><i>Francisella</i></b> Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid

Unique <b><i>Francisella</i></b> Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid

Metabolic Reprogramming of Host Cells by Virulent Francisella tularensis for Optimal Replication and Modulation of Inflammation

A tug-of-war between the host and the pathogen generates strategic hotspots for the development of novel therapeutic interventions against infectious diseases

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