Human patients with mitochondrial diseases are more susceptible to bacterial infections, particularly of the respiratory tract. To investigate the susceptibility of mitochondrially diseased cells to an intracellular bacterial respiratory pathogen, we exploited the advantages of Dictyostelium discoideum as an established model for mitochondrial disease and for Legionella pneumophila pathogenesis. Legionella infection of macrophages involves recruitment of mitochondria to the Legionella-containing phagosome. We confirm here that this also occurs in Dictyostelium and investigate the effect of mitochondrial dysfunction on host cell susceptibility to Legionella. In mitochondrially diseased Dictyostelium strains, the pathogen was taken up at normal rates, but it grew faster and reached counts that were twofold higher than in the wild type host. We previously reported that other mitochondrial disease phenotypes for Dictyostelium are due to activity of an energy-sensing cellular alarm protein, AMP-activated protein kinase (AMPK). Here we show that the increased ability of mitochondrially diseased cells to support Legionella proliferation is suppressed by antisense-inhibiting expression of the catalytic AMPK _ subunit. Conversely, mitochondrial dysfunction is phenocopied and intracellular Legionella growth enhanced, by overexpressing an active form of AMPK_ in otherwise normal cells. These results indicate that AMPK signalling in response to mitochondrial dysfunction enhances Legionella proliferation in host cells.

Legionella pneumophila multiplication is enhanced by chronic AMPK signalling in mitochondrially diseased cells

BOZZARO, Salvatore;
2009

Abstract

Human patients with mitochondrial diseases are more susceptible to bacterial infections, particularly of the respiratory tract. To investigate the susceptibility of mitochondrially diseased cells to an intracellular bacterial respiratory pathogen, we exploited the advantages of Dictyostelium discoideum as an established model for mitochondrial disease and for Legionella pneumophila pathogenesis. Legionella infection of macrophages involves recruitment of mitochondria to the Legionella-containing phagosome. We confirm here that this also occurs in Dictyostelium and investigate the effect of mitochondrial dysfunction on host cell susceptibility to Legionella. In mitochondrially diseased Dictyostelium strains, the pathogen was taken up at normal rates, but it grew faster and reached counts that were twofold higher than in the wild type host. We previously reported that other mitochondrial disease phenotypes for Dictyostelium are due to activity of an energy-sensing cellular alarm protein, AMP-activated protein kinase (AMPK). Here we show that the increased ability of mitochondrially diseased cells to support Legionella proliferation is suppressed by antisense-inhibiting expression of the catalytic AMPK _ subunit. Conversely, mitochondrial dysfunction is phenocopied and intracellular Legionella growth enhanced, by overexpressing an active form of AMPK_ in otherwise normal cells. These results indicate that AMPK signalling in response to mitochondrial dysfunction enhances Legionella proliferation in host cells.
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http://www.personalweb.unito.it/salvatore.bozzaro
DICTYOSTELIUM; LEGIONELLA; MITOCHONDRIAL DISEASES; AMPK; HOST-PATHOGEN INTERACTIONS
Francione L; Smith PS; Accari S; Taylor PT; BokkoPB; Bozzaro S; Beech PL;and Fisher PR
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/59221
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