title: 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.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: M Indriati
authors.initials: MI
authors.lastname: Hood
authors.forename: Roman
authors.initials: R
authors.lastname: Uzhachenko
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.forename: Alla V
authors.initials: AV
authors.lastname: Ivanova
mesh_terms: D000151:Acinetobacter Infections / Q000276:immunology* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D020381:Interleukin-17; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C543627:Tusc2 protein, mouse; D016753:Interleukin-10; C546843:mTOR protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
references.citation: Clin Cancer Res. 2008 Jan 1;14(1):41-7
references.pmid: 18172250
references.citation: PLoS Pathog. 2009 Oct;5(10):e1000639
references.pmid: 19876394
references.citation: J Immunol. 2012 May 15;188(10):5003-11
references.pmid: 22491245
references.citation: Blood. 2009 Sep 24;114(13):2619-22
references.pmid: 19541821
references.citation: Infect Immun. 2011 Aug;79(8):3317-27
references.pmid: 21576323
references.citation: Infect Immun. 2010 May;78(5):1952-62
references.pmid: 20194595
references.citation: Science. 2004 Mar 5;303(5663):1532-5
references.pmid: 15001782
references.citation: Jpn J Infect Dis. 2008 Sep;61(5):339-42
references.pmid: 18806338
references.citation: Blood. 2009 May 14;113(20):4930-41
references.pmid: 19286998
references.citation: J Allergy Clin Immunol. 2011 May;127(5):1243-52.e7
references.pmid: 21376380
references.citation: Nat Rev Immunol. 2011 Jun;11(6):389-402
references.pmid: 21597473
references.citation: PLoS One. 2012;7(12):e52969
references.pmid: 23285237
references.citation: PLoS Pathog. 2012;8(12):e1003068
references.pmid: 23236280
references.citation: PLoS One. 2010 Apr 07;5(4):e10033
references.pmid: 20383325
references.citation: Microbes Infect. 2009 Oct;11(12):946-55
references.pmid: 19573619
references.citation: Mol Cancer. 2009 Oct 24;8:91
references.pmid: 19852844
references.citation: Infect Immun. 2009 Mar;77(3):1015-21
references.pmid: 19103777
references.citation: Dev Cell. 2010 Dec 14;19(6):845-57
references.pmid: 21145500
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G275-82
references.pmid: 19940030
references.citation: Infect Immun. 2007 Dec;75(12):5597-608
references.pmid: 17908807
references.citation: Int J Antimicrob Agents. 2011 Apr;37(4):291-5
references.pmid: 21382699
references.citation: J Immunol. 2003 Jun 15;170(12):6257-65
references.pmid: 12794158
references.citation: Nat Genet. 2000 Dec;26(4):435-9
references.pmid: 11101840
references.citation: EMBO J. 2011 Nov 15;30(24):4860-73
references.pmid: 22085932
references.citation: Blood. 2012 Oct 11;120(15):3118-25
references.pmid: 22919032
references.citation: Clin Exp Immunol. 2008 Sep;153(3):420-8
references.pmid: 18647324
references.citation: J Pathol. 2012 Aug;227(4):456-69
references.pmid: 22513871
references.citation: Mol Cell Biol. 2004 Feb;24(3):1007-21
references.pmid: 14729949
references.citation: Nature. 2011 Apr 28;472(7344):476-80
references.pmid: 21525932
references.citation: Int Immunopharmacol. 2011 Sep;11(9):1378-83
references.pmid: 21496497
references.citation: J Biol Chem. 2007 Feb 9;282(6):3507-19
references.pmid: 17158870
references.citation: Antioxid Redox Signal. 2014 Apr 1;20(10):1533-47
references.pmid: 24328503
references.citation: Cancer Res. 2000 Apr 1;60(7):1949-60
references.pmid: 10766185
references.citation: Circulation. 2003 Jan 28;107(3):388-90
references.pmid: 12551860
references.citation: Chemotherapy. 2010;56(4):275-9
references.pmid: 20693798
references.citation: Clin Infect Dis. 2005 Sep 15;41(6):848-54
references.pmid: 16107985
references.citation: J Exp Med. 2006 Oct 2;203(10):2271-9
references.pmid: 16982811
references.citation: Biochem Pharmacol. 2006 Nov 30;72(11):1493-505
references.pmid: 16723122
references.citation: J Immunol. 2001 Aug 1;167(3):1592-600
references.pmid: 11466381
references.citation: Blood. 2009 Jun 18;113(25):6419-27
references.pmid: 19221037
references.citation: Aging (Albany NY). 2010 Aug;2(8):514-8
references.pmid: 20689155
references.citation: Am J Respir Crit Care Med. 2008 May 1;177(9):959-69
references.pmid: 18263801
references.citation: FEBS Lett. 2010 Apr 16;584(8):1437-42
references.pmid: 20227410
references.citation: J Pathol. 2007 Apr;211(5):591-601
references.pmid: 17318811
references.citation: Int J Antimicrob Agents. 2009 Mar;33(3):266-71
references.pmid: 19091522
references.citation: J Immunol. 2003 Jan 15;170(2):1091-8
references.pmid: 12517978
references.citation: Microbiol Immunol. 2012 Feb;56(2):107-16
references.pmid: 22145920
references.citation: Nature. 2011 Aug 21;477(7363):220-4
references.pmid: 21857682
references.citation: J Leukoc Biol. 2011 Jun;89(6):945-53
references.pmid: 21393420
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Jul;287(1):L143-52
references.pmid: 15047567
references.citation: PLoS One. 2012;7(6):e40019
references.pmid: 22768201
references.citation: Cytokine. 2006 Aug;35(3-4):135-42
references.pmid: 16971137