Loss of mitochondrial protein Fus1 augments host resistance to Acinetobacter baumannii infection.

Abstract

Fus1 is a tumor suppressor protein with recently described immunoregulatory functions. Although its role in sterile inflammation is being elucidated, its role in regulating immune responses to infectious agents has not been examined. We used here a murine model of Acinetobacter baumannii pneumonia to identify the role of Fus1 in antibacterial host defenses. We found that the loss of Fus1 in mice results in significantly increased resistance to A. baumannii pneumonia. We observed earlier and more robust recruitment of neutrophils and macrophages to the lungs of infected Fus1(-/-) mice, with a concomitant increase in phagocytosis of invading bacteria and more rapid clearance. Such a prompt and enhanced immune response to bacterial infection in Fus1(-/-) mice stems from early activation of proinflammatory pathways (NF-κB and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin [mTOR]), most likely due to significantly increased mitochondrial membrane potential and mitochondrial reactive oxygen species production. Significant early upregulation of interleukin-17 (IL-17) in Fus1(-/-) immune cells was also observed, together with significant downregulation of IL-10. Depletion of neutrophils eliminates the enhanced antibacterial defenses of the Fus1(-/-) mice, suggesting that ultimately it is the enhanced immune cell recruitment that mediates the increased resistance of Fus1(-/-) mice to A. baumannii pneumonia. Taken together, our data define the novel role for Fus1 in the immune response to A. baumannii pneumonia and highlight new avenues for immune modulating therapeutic targets for this treatment-resistant nosocomial pathogen.

• Authors: M Indriati Hood, Roman Uzhachenko, Kelli Boyd, Eric P Skaar, Alla V Ivanova
• Journal: Infection and immunity (Infect Immun) Vol. 81 Issue 12 Pg. 4461-9 (Dec 2013) ISSN: 1098-5522 [Electronic] United States
• PMID: 24042119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-17
• NF-kappa B
• Reactive Oxygen Species
• Tumor Suppressor Proteins
• Tusc2 protein, mouse
• Interleukin-10
• mTOR protein, mouse
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Acinetobacter Infections (immunology, microbiology)
• Acinetobacter baumannii (genetics, immunology, pathogenicity)
• Animals
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Interleukin-10 (biosynthesis)
• Interleukin-17 (biosynthesis)
• Lung (immunology, microbiology)
• Macrophages (immunology)
• Male
• Membrane Potential, Mitochondrial (genetics, immunology)
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Neutrophils (immunology)
• Phosphatidylinositol 3-Kinase (metabolism)
• Pneumonia, Bacterial (immunology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (immunology, metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Tumor Suppressor Proteins (deficiency, genetics)