title: Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.
abstract: Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics "emergency hematopoiesis," a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.
authors.affiliation: Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Napier
authors.affiliation: Immunology and Molecular Pathogenesis Graduate Program, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Norris
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Alyson
authors.initials: A
authors.lastname: Swimm
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Giver
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Wayne A C
authors.initials: WA
authors.lastname: Harris
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America; Center for Cystic Fibrosis Research, Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America; Institut de Génétique Moléculaire de Montpellier (IGMM), CNRS UMR5535, Université Montpellier, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Laval
authors.affiliation: Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Napier
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Gopi
authors.initials: G
authors.lastname: Patel
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Crump
authors.affiliation: MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.affiliation: MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America; Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America; Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri, United States of America.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Buller
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America; Yerkes National Primate Research Center, Atlanta, Georgia, United States of America; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America; Center for Cystic Fibrosis Research, Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Rabindra
authors.initials: R
authors.lastname: Tirouvanziam
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D005603:Francisella / Q000276:immunology*; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007958:Leukocyte Count; D051379:Mice; D038042:Myelopoiesis / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*
chemical_list: D000068877:Imatinib Mesylate
references.citation: Med Res Rev. 2000 Jan;20(1):28-57
references.pmid: 10608920
references.citation: EXS. 2000;89:123-39
references.pmid: 10997286
references.citation: N Engl J Med. 2001 Apr 5;344(14):1031-7
references.pmid: 11287972
references.citation: Blood. 2001 Oct 1;98(7):2039-42
references.pmid: 11567987
references.citation: Semin Hematol. 2003 Jan;40(1):50-8
references.pmid: 12563611
references.citation: Exp Hematol. 2003 Feb;31(2):109-17
references.pmid: 12591275
references.citation: Hematol Oncol. 2003 Jun;21(2):67-75
references.pmid: 12802811
references.citation: Blood. 1992 Dec 15;80(12):3044-50
references.pmid: 1281687
references.citation: Blood. 2004 Jan 15;103(2):523-9
references.pmid: 12969987
references.citation: EMBO J. 2003 Oct 15;22(20):5471-9
references.pmid: 14532119
references.citation: Nat Rev Mol Cell Biol. 2004 Jan;5(1):33-44
references.pmid: 14708008
references.citation: Blood. 2004 Jul 15;104(2):565-71
references.pmid: 15054039
references.citation: Mol Biol Cell. 2004 Aug;15(8):3520-9
references.pmid: 15155808
references.citation: J Clin Invest. 2004 Aug;114(3):379-88
references.pmid: 15286804
references.citation: Blood. 2005 Apr 15;105(8):3127-32
references.pmid: 15637141
references.citation: Blood. 2005 May 15;105(10):3987-94
references.pmid: 15665117
references.citation: Cell. 2005 Apr 22;121(2):295-306
references.pmid: 15851035
references.citation: Nat Med. 2005 Jul;11(7):731-9
references.pmid: 15980865
references.citation: J Virol. 2005 Sep;79(18):11943-51
references.pmid: 16140770
references.citation: J Exp Med. 2005 Dec 19;202(12):1715-24
references.pmid: 16365150
references.citation: Cell. 2006 Jan 13;124(1):119-31
references.pmid: 16413486
references.citation: Nat Rev Immunol. 2006 Feb;6(2):93-106
references.pmid: 16491134
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3153-8
references.pmid: 16492761
references.citation: J Clin Invest. 2006 Apr;116(4):916-28
references.pmid: 16543948
references.citation: J Immunol. 2006 Aug 1;177(3):1864-71
references.pmid: 16849498
references.citation: Annu Rev Immunol. 2007;25:101-37
references.pmid: 17090225
references.citation: N Engl J Med. 1991 Jul 18;325(3):164-70
references.pmid: 1711156
references.citation: J Immunol. 2007 Feb 15;178(4):2028-37
references.pmid: 17277106
references.citation: Gastroenterology. 2007 Apr;132(4):1309-19
references.pmid: 17408661
references.citation: Ann N Y Acad Sci. 2007 Jun;1106:64-75
references.pmid: 17442778
references.citation: Cell Microbiol. 2007 Nov;9(11):2644-57
references.pmid: 17587335
references.citation: Orphanet J Rare Dis. 2007 Jul 26;2:34
references.pmid: 17655751
references.citation: J Clin Invest. 2007 Aug;117(8):2030-2
references.pmid: 17671635
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):231-41
references.pmid: 18073771
references.citation: J Immunol. 2008 Feb 15;180(4):2045-53
references.pmid: 18250409
references.citation: Blood. 2008 Apr 15;111(8):4022-8
references.pmid: 18256322
references.citation: PLoS Pathog. 2008 Mar 07;4(3):e1000021
references.pmid: 18369471
references.citation: PLoS Pathog. 2008 Mar 21;4(3):e1000031
references.pmid: 18369477
references.citation: Cancer Chemother Pharmacol. 2009 Jan;63(2):229-38
references.pmid: 18398615
references.citation: Cytokine. 2008 Jun;42(3):277-88
references.pmid: 18400509
references.citation: Infect Immun. 2009 Jan;77(1):60-9
references.pmid: 18936177
references.citation: Am J Pathol. 2008 Dec;173(6):1693-701
references.pmid: 18988802
references.citation: Cell. 2008 Dec 12;135(6):1118-29
references.pmid: 19062086
references.citation: Cell Host Microbe. 2009 Feb 19;5(2):114-22
references.pmid: 19218083
references.citation: Blood. 2009 May 7;113(19):4711-9
references.pmid: 19264920
references.citation: J Cell Sci. 2009 Oct 1;122(Pt 19):3441-54
references.pmid: 19759284
references.citation: J Virol. 2010 May;84(9):4243-51
references.pmid: 20181697
references.citation: J Innate Immun. 2010;2(3):216-27
references.pmid: 20375550
references.citation: J Clin Invest. 2010 Jul;120(7):2423-31
references.pmid: 20516641
references.citation: PLoS Pathog. 2010 Jun 17;6(6):e1000956
references.pmid: 20585556
references.citation: J Virol. 2011 Jan;85(1):21-31
references.pmid: 20962097
references.citation: J Appl Physiol (1985). 2011 Feb;110(2):340-51
references.pmid: 20966192
references.citation: Leukemia. 2011 Feb;25(2):211-7
references.pmid: 21079612
references.citation: J Clin Invest. 2011 Jan;121(1):396-409
references.pmid: 21157039
references.citation: J Immunol. 2011 Jun 15;186(12):7110-9
references.pmid: 21555529
references.citation: Nat Med. 2011 Aug 28;17(9):1094-100
references.pmid: 21873989
references.citation: Acta Neurol Scand. 2012 Jan;125(1):8-15
references.pmid: 21883097
references.citation: J Exp Med. 2011 Oct 24;208(11):2251-62
references.pmid: 21967766
references.citation: Cell Host Microbe. 2011 Nov 17;10(5):475-85
references.pmid: 22100163
references.citation: Blood. 2012 Feb 2;119(5):1123-9
references.pmid: 22160483
references.citation: Blood. 2012 Mar 1;119(9):1981-7
references.pmid: 22228624
references.citation: Cell. 2012 Feb 3;148(3):434-46
references.pmid: 22304914
references.citation: Sci Transl Med. 2012 Feb 29;4(123):123ra24
references.pmid: 22378924
references.citation: Future Microbiol. 2012 Apr;7(4):431-5
references.pmid: 22439718
references.citation: Mol Cell Biol. 2012 Aug;32(15):3176-86
references.pmid: 22665498
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14019-23
references.pmid: 22891346
references.citation: J Immunol. 2012 Oct 15;189(8):4069-78
references.pmid: 22988030
references.citation: Cancer Immunol Immunother. 2013 Apr;62(4):715-26
references.pmid: 23184338
references.citation: Nat Rev Immunol. 2013 Mar;13(3):159-75
references.pmid: 23435331
references.citation: Cell Rep. 2013 May 30;3(5):1539-52
references.pmid: 23707063
references.citation: PLoS Pathog. 2013;9(6):e1003408
references.pmid: 23754944
references.citation: Curr Opin Pharmacol. 2013 Aug;13(4):641-5
references.pmid: 23849093
references.citation: J Exp Med. 2014 Feb 10;211(2):217-31
references.pmid: 24446491
references.citation: N Engl J Med. 1988 Jun 2;318(22):1414-22
references.pmid: 2452983
references.citation: Nature. 2014 Jul 3;511(7507):99-103
references.pmid: 24990750
references.citation: Immunol Rev. 2015 Mar;264(1):344-62
references.pmid: 25703571
references.citation: Am J Respir Crit Care Med. 2015 May 15;191(10):1185-96
references.pmid: 25730547
references.citation: Development. 1993 Mar;117(3):1089-98
references.pmid: 7686845
references.citation: Blood. 1993 Jul 15;82(2):445-55
references.pmid: 7687160
references.citation: Blood. 1993 Aug 1;82(3):762-70
references.pmid: 7687891
references.citation: Infect Immun. 1994 Jul;62(7):2779-83
references.pmid: 8005668
references.citation: Exp Hematol. 1993 Feb;21(2):206-19
references.pmid: 8425559
references.citation: Cancer Res. 1996 Jan 1;56(1):100-4
references.pmid: 8548747
references.citation: Infect Immun. 1996 Aug;64(8):3288-93
references.pmid: 8757866
references.citation: Infect Immun. 1997 Feb;65(2):630-5
references.pmid: 9009323
references.citation: Blood. 1997 Dec 15;90(12):4947-52
references.pmid: 9389713
references.citation: Haematologica. 1997 Sep-Oct;82(5):606-16
references.pmid: 9407734