title: Dectin-1 is required for resistance to coccidioidomycosis in mice.
abstract: We assessed the role of Dectin-1 in the immune response to the pathogenic fungus Coccidioides, both in vitro and in vivo, using mice with a targeted mutation in Clec7a. Elicited peritoneal macrophages responded to formalin-killed spherules (FKS) and alkali-treated FKS by secreting proinflammatory cytokines in a Dectin-1- and β-glucan-dependent manner. The responses of bone marrow-derived dendritic cells (BMDC) to the same stimulants were more complex; interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) secretion was independent of Dectin-1, while IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were largely but not entirely dependent on Dectin-1. After intranasal infection, Dectin-1(-/-) mice had lower concentrations of IL-12p70, gamma interferon (IFN-γ), IL-1β, and the Th17 cytokines IL-22, IL-23, and 17A in the lung lavage fluid, which may explain why they were significantly more susceptible to pulmonary coccidioidomycosis two weeks after infection. The Dectin-1 mutation was even more deleterious in (B6 × DBA/2)F(2) mice, which are more resistant to coccidioidomycosis than B6 mice by virtue of protective genes from DBA/2, a genetically resistant strain. We also found that two susceptible strains of mice (B6 and BALB/c) expressed much less Dectin-1 in their lungs than did resistant DBA/2 mice. We conclude that Dectin-1 is necessary for resistance to Coccidioides immitis, that Dectin-1 promotes both Th1 and Th17 protective immune responses to this infection, and that there is a correlation between expression of Dectin-1 by the inflammatory infiltrate and resistance to coccidioidomycosis. IMPORTANCE Coccidioidomycosis is a fungal infection endemic in the southwestern United States and neighboring Mexico, causing ~150,000 lung infections in people and resulting in ~17,000 hospitalizations annually in California alone. Very little is known about innate immunity to this fungus. This paper shows that Dectin-1, the primary β-glucan receptor on myeloid cells, is required for resistance to this pathogen. Dectin-1 is part of the innate immune system, and it is needed to direct the acquired immune response toward into a pathway that will lead to macrophage activation. Lungs from infected mice lacking Dectin-1 had lower concentrations of Th1 and Th17 cytokines, two cytokine pathways that are very important for acquired T cell immunity to Coccidioides spp. This is the first demonstration that Dectin-1 is required for host resistance to a dimorphic, primary pathogenic fungus.
authors: Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine, San Diego, California, USA.
authors: Suganya
authors: S
authors: Viriyakosol
authors: Maria del Pilar
authors: Mdel P
authors: Jimenez
authors: Michael A
authors: MA
authors: Gurney
authors: Mark E
authors: ME
authors: Ashbaugh
authors: Joshua
authors: J
authors: Fierer
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D003045:Coccidioides / Q000276:immunology* / Q000472:pathogenicity*; D003047:Coccidioidomycosis / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D060467:Disease Resistance; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D037181:Lectins, C-Type; D000099181:Dectin-1
references: Blood. 2005 Oct 1;106(7):2543-50
references: 15956283
references: Nat Immunol. 2007 Jan;8(1):31-8
references: 17159984
references: BMC Microbiol. 2012 Sep 24;12:218
references: 23006927
references: Nat Immunol. 2012 Jan 22;13(3):246-54
references: 22267217
references: J Infect Dis. 2006 May 1;193(9):1323-31
references: 16586371
references: Medicine (Baltimore). 1975 Sep;54(5):377-95
references: 1099399
references: J Bacteriol. 1961 Nov;82:714-23
references: 14483753
references: J Immunol. 1996 Feb 1;156(3):1235-46
references: 8558003
references: Infect Immun. 1988 Oct;56(10):2686-94
references: 3138180
references: N Engl J Med. 2009 Oct 29;361(18):1760-7
references: 19864674
references: Immunity. 2007 May;26(5):605-16
references: 17462920
references: Mayo Clin Proc. 2011 Jan;86(1):63-9
references: 21193657
references: Infect Immun. 1983 Aug;41(2):728-34
references: 6874073
references: Infect Immun. 2005 Mar;73(3):1553-60
references: 15731053
references: Cell Host Microbe. 2011 May 19;9(5):436-43
references: 21575914
references: Immunity. 2005 Apr;22(4):507-17
references: 15845454
references: Nat Immunol. 2007 Jan;8(1):39-46
references: 17159982
references: Infect Immun. 1995 Sep;63(9):3514-9
references: 7642285
references: Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1366-70
references: 17227865
references: J Immunol. 2006 May 1;176(9):5513-8
references: 16622020
references: J Bacteriol. 1970 Aug;103(2):525-6
references: 5432015
references: Mamm Genome. 2011 Feb;22(1-2):55-65
references: 20700596
references: Res Immunol. 1998 May-Jun;149(4-5):417-28; discussion 506-7
references: 9720959
references: Cell Microbiol. 2008 Oct;10(10):2058-66
references: 18549457
references: Mycologia. 2002 Jan-Feb;94(1):73-84
references: 21156479
references: BMC Microbiol. 2011 Apr 11;11:71
references: 21481258
references: Infect Immun. 1988 Jan;56(1):13-7
references: 3335400
references: Trends Microbiol. 2006 Oct;14(10):426-7
references: 16893649
references: Gene. 2001 Jul 11;272(1-2):51-60
references: 11470510
references: Nat Rev Immunol. 2011 Apr;11(4):275-88
references: 21394104
references: Clin Infect Dis. 2001 Mar 1;32(5):708-15
references: 11229838
references: J Immunol Methods. 1999 Feb 1;223(1):77-92
references: 10037236
references: Microbiol Immunol. 2007;51(11):1115-9
references: 18037789
references: Genes Immun. 2008 Jun;9(4):338-48
references: 18418396
references: Annu Rev Immunol. 2011;29:1-21
references: 20936972
references: J Infect Dis. 2011 Oct 1;204(7):1138-45
references: 21881131
references: Science. 2012 Jun 8;336(6086):1314-7
references: 22674328
references: PLoS Pathog. 2010 Jul 01;6:e1000976
references: 20617171
references: Blood. 1996 Mar 15;87(6):2095-147
references: 8630372
references: Infect Immun. 2006 Jun;74(6):3387-95
references: 16714569
references: Methods Enzymol. 2008;437:521-38
references: 18433645
references: J Immunol. 2003 Nov 1;171(9):4569-73
references: 14568930
references: PLoS Med. 2005 Jan;2(1):e2
references: 15696207
references: Med Mycol. 2001;39 Suppl 1:31-40
references: 11800267
references: Infect Immun. 1999 Jun;67(6):2916-9
references: 10338499
references: Ann N Y Acad Sci. 2012 Apr;1253:149-58
references: 22288724
references: Curr Opin Immunol. 2012 Aug;24(4):449-58
references: 22613091
references: PLoS One. 2010 Oct 18;5(10):e13418
references: 20976143
references: Trends Microbiol. 2002 Feb;10(2):80-7
references: 11827809
references: J Immunol. 2009 Apr 15;182(8):4938-46
references: 19342673
references: Infect Immun. 1983 Jun;40(3):912-6
references: 6852925
references: J Leukoc Biol. 2007 Aug;82(2):253-8
references: 17475782
references: Trends Microbiol. 2006 Apr;14(4):183-9
references: 16517165
references: Cell Mol Immunol. 2012 May;9(3):276-86
references: 22543832
references: Curr Top Med Mycol. 1988;2:199-238
references: 3288356
references: Infect Immun. 1998 Sep;66(9):4397-402
references: 9712793
references: Am J Med. 1993 Mar;94(3):235-40
references: 8095771
references: J Clin Invest. 2011 Feb;121(2):554-68
references: 21206087
references: Immunobiology. 2011 Nov;216(11):1184-91
references: 21742403
references: Nature. 2001 Sep 6;413(6851):36-7
references: 11544516
references: Immunity. 2010 May 28;32(5):681-91
references: 20493731
references: J Exp Med. 2003 May 5;197(9):1107-17
references: 12719479
references: Clin Microbiol Rev. 1990 Jul;3(3):247-68
references: 2200605
references: N Engl J Med. 1979 Aug 16;301(7):358-61
references: 460324
references: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1228-33
references: 19164571
references: Eur J Immunol. 2008 Feb;38(2):500-6
references: 18200499
references: Nat Immunol. 2012 Sep;13(9):817-22
references: 22910394
references: Emerg Infect Dis. 1996 Jul-Sep;2(3):192-9
references: 8903229
references: Eur J Immunol. 2008 Dec;38(12):3274-81
references: 19039774