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• W1987746874 abstract "To determine whether TLR9 signaling contributes to the development of the adaptive immune response to cryptococcal infection, wild-type (TLR9+/+) and TLR9 knockout (TLR9−/−) BALB/c mice were infected intratracheally with 104 C. neoformans 52D. We evaluated 1) organ microbial burdens, 2) pulmonary leukocyte recruitment, 3) pulmonary and systemic cytokine induction, and 4) macrophage activation profiles. TLR9 deletion did not affect pulmonary growth during the innate phase, but profoundly impaired pulmonary clearance during the adaptive phase of the immune response (a 1000-fold difference at week 6). The impaired clearance in TLR9−/− mice was associated with: 1) significantly reduced CD4+, CD8+ T cell, and CD19+ B cell recruitment into the lungs; 2) defects in Th polarization indicated by altered cytokine responses in the lungs, lymphonodes, and spleen; and 3) diminished macrophage accumulation and altered activation profile, including robust up-regulation of Arg1 and FIZZ1 (indicators of alternative activation) and diminished induction of inducible nitric oxide synthase (an indicator of classical activation). Histological analysis revealed defects in granuloma formation and increased numbers of intracellular yeast residing within macrophages in the lungs of TLR9−/− mice. We conclude that TLR9 signaling plays an important role in the development of robust protective immunity, proper recruitment and function of effector cells (lymphocytes and macrophages), and, ultimately, effective cryptococcal clearance from the infected lungs. To determine whether TLR9 signaling contributes to the development of the adaptive immune response to cryptococcal infection, wild-type (TLR9+/+) and TLR9 knockout (TLR9−/−) BALB/c mice were infected intratracheally with 104 C. neoformans 52D. We evaluated 1) organ microbial burdens, 2) pulmonary leukocyte recruitment, 3) pulmonary and systemic cytokine induction, and 4) macrophage activation profiles. TLR9 deletion did not affect pulmonary growth during the innate phase, but profoundly impaired pulmonary clearance during the adaptive phase of the immune response (a 1000-fold difference at week 6). The impaired clearance in TLR9−/− mice was associated with: 1) significantly reduced CD4+, CD8+ T cell, and CD19+ B cell recruitment into the lungs; 2) defects in Th polarization indicated by altered cytokine responses in the lungs, lymphonodes, and spleen; and 3) diminished macrophage accumulation and altered activation profile, including robust up-regulation of Arg1 and FIZZ1 (indicators of alternative activation) and diminished induction of inducible nitric oxide synthase (an indicator of classical activation). Histological analysis revealed defects in granuloma formation and increased numbers of intracellular yeast residing within macrophages in the lungs of TLR9−/− mice. We conclude that TLR9 signaling plays an important role in the development of robust protective immunity, proper recruitment and function of effector cells (lymphocytes and macrophages), and, ultimately, effective cryptococcal clearance from the infected lungs. C. neoformans is a leading cause of fatal mycosis in HIV-positive individuals around the globe. Incidence of C. neoformans infection is increasing in organ transplant recipients, patients with hematological malignancies, and those undergoing immunosuppressive therapies. Cryptococcosis patients are affected predominantly by encapsulated strains of C. neoformans,1Bottone EJ Toma M Johansson BE Wormser GP Capsule-deficient Cryptococcus neoformans in AIDS patients.Lancet. 1985; 1: 400Abstract PubMed Scopus (19) Google Scholar, 2Nishikawa MM Lazera MS Barbosa GG Trilles L Balassiano BR Macedo RC Bezerra CC Perez MA Cardarelli P Wanke B Serotyping of 467 Cryptococcus neoformans isolates from clinical and environmental sources in Brazil: analysis of host and regional patterns.J Clin Microbiol. 2003; 41: 73-77Crossref PubMed Scopus (83) Google Scholar, 3Perfect JR Cryptococcus neoformans: a sugar-coated killer with designer genes.FEMS Immunol Med Microbiol. 2005; 45: 395-404Crossref PubMed Scopus (81) Google Scholar while nonencapsulated strains are only rarely isolated from severely immunocompromised patients1Bottone EJ Toma M Johansson BE Wormser GP Capsule-deficient Cryptococcus neoformans in AIDS patients.Lancet. 1985; 1: 400Abstract PubMed Scopus (19) Google Scholar, 4Attal HC Grover S Bansal MP Chaubey BS Joglekar VK Capsule deficient Cryptococcus neoformans an unusual clinical presentation.J Assoc Physicians India. 1983; 31: 49-51PubMed Google Scholar, 5Bava J Solari R Isla G Troncoso A Atypical forms of Cryptococcus neoformans in CSF of an AIDS patient.J Infect Dev Ctries. 2008; 2: 403-405Crossref PubMed Scopus (8) Google Scholar, 6Mackenzie DW Hay RJ Capsule-deficient Cryptococcus neoformans in AIDS patients.Lancet. 1985; 1: 642Abstract PubMed Google Scholar and can be cleared by the innate immune system in laboratory infection models.7Barluzzi R Brozzetti A Delfino D Bistoni F Blasi E Role of the capsule in microglial cell-Cryptococcus neoformans interaction: impairment of antifungal activity but not of secretory functions.Med Mycol. 1998; 36: 189-197PubMed Google Scholar, 8Fromtling RA Shadomy HJ Jacobson ES Decreased virulence in stable, acapsular mutants of Cryptococcus neoformans.Mycopathologia. 1982; 79: 23-29Crossref PubMed Scopus (133) Google Scholar, 9Wilder JA Olson GK Chang YC Kwon-Chung KJ Lipscomb MF Complementation of a capsule deficient Cryptococcus neoformans with CAP64 restores virulence in a murine lung infection.Am J Respir Cell Mol Biol. 2002; 26: 306-314Crossref PubMed Scopus (28) Google Scholar Lack of CD4+ or CD8+ lymphocytes is the most common trigger for progressive/persistent cryptococcosis in both patients and animal models of infection.10Huffnagle GB Lipscomb MF Lovchik JA Hoag KA Street NE The role of CD4+ and CD8+ T cells in the protective inflammatory response to a pulmonary cryptococcal infection.J Leukoc Biol. 1994; 55: 35-42PubMed Google Scholar, 11Arora S Hernandez Y Erb-Downward JR McDonald RA Toews GB Huffnagle GB Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis.J Immunol. 2005; 174: 6346-6356PubMed Google Scholar, 12Lindell DM Moore TA McDonald RA Toews GB Huffnagle GB Generation of antifungal effector CD8+ T cells in the absence of CD4+ T cells during Cryptococcus neoformans infection.J Immunol. 2005; 174: 7920-7928PubMed Google Scholar, 13Lindell DM Moore TA McDonald RA Toews GB Huffnagle GB Distinct compartmentalization of CD4+ T-cell effector function versus proliferative capacity during pulmonary cryptococcosis.Am J Pathol. 2006; 168: 847-855Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar The development of protective immunity in the lungs is associated with the arrival of effector T cells (CD4+ and CD8+) into the lungs, which coincides with positive delayed-type hypersensitivity reactivity to cryptococcal antigens.14Buchanan KL Murphy JW Kinetics of cellular infiltration and cytokine production during the efferent phase of a delayed-type hypersensitivity reaction.Immunology. 1997; 90: 189-197Crossref PubMed Scopus (41) Google Scholar, 15Buchanan KL Fidel Jr, PL Murphy JW Effects of Cryptococcus neoformans-specific suppressor T cells on the amplified anticryptococcal delayed-type hypersensitivity response.Infect Immun. 1991; 59: 29-35PubMed Google Scholar In contrast with the pivotal role of T cells, the role of B cells during C. neoformans clearance is less apparent.16Aguirre KM Johnson LL A role for B cells in resistance to Cryptococcus neoformans in mice.Infect Immun. 1997; 65: 525-530PubMed Google Scholar, 17Fung PY Murphy JW In vitro interactions of immune lymphocytes and Cryptococcus neoformans.Infect Immun. 1982; 36: 1128-1138PubMed Google Scholar, 18Vecchiarelli A The cellular responses induced by the capsular polysaccharide of Cryptococcus neoformans differ depending on the presence or absence of specific protective antibodies.Curr Mol Med. 2005; 5: 413-420Crossref PubMed Scopus (30) Google Scholar, 19Beenhouwer DO Shapiro S Feldmesser M Casadevall A Scharff MD Both Th1 and Th2 cytokines affect the ability of monoclonal antibodies to protect mice against Cryptococcus neoformans.Infect Immun. 2001; 69: 6445-6455Crossref PubMed Scopus (88) Google Scholar, 20Maitta RW Datta K Chang Q Luo RX Witover B Subramaniam K Pirofski LA Protective and nonprotective human immunoglobulin M monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan manifest different specificities and gene use profiles.Infect Immun. 2004; 72: 4810-4818Crossref PubMed Scopus (49) Google Scholar, 21Torosantucci A Chiani P Bromuro C De Bernardis F Palma AS Liu Y Mignogna G Maras B Colone M Stringaro A Zamboni S Feizi T Cassone A Protection by anti-beta-glucan antibodies is associated with restricted beta-1,3 glucan binding specificity and inhibition of fungal growth and adherence.PLoS One. 2009; 4: e5392Crossref PubMed Scopus (166) Google Scholar Successful clearance of C. neoformans is also associated with an adaptive Th1 immune response characterized by antigen driven production of type 1 cytokines (interferon [IFN]-γ and tumor necrosis factor [TNF]-α) and containment of C. neoformans within granuloma-like inflammatory infiltrates.22Chen GH McDonald RA Wells JC Huffnagle GB Lukacs NW Toews GB The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans.Infect Immun. 2005; 73: 1788-1796Crossref PubMed Scopus (70) Google Scholar, 23Chen GH McNamara DA Hernandez Y Huffnagle GB Toews GB Olszewski MA Inheritance of immune polarization patterns is linked to resistance versus susceptibility to Cryptococcus neoformans in a mouse model.Infect Immun. 2008; 76: 2379-2391Crossref PubMed Scopus (71) Google Scholar, 24Decken K Kohler G Palmer-Lehmann K Wunderlin A Mattner F Magram J Gately MK Alber G Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.Infect Immun. 1998; 66: 4994-5000Crossref PubMed Google Scholar, 25Lovchik JA Lyons CR Lipscomb MF A role for gamma interferon-induced nitric oxide in pulmonary clearance of Cryptococcus neoformans.Am J Respir Cell Mol Biol. 1995; 13: 116-124Crossref PubMed Scopus (76) Google Scholar, 26Traynor TR Kuziel WA Toews GB Huffnagle GB CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection.J Immunol. 2000; 164: 2021-2027PubMed Google Scholar In contrast, Th2 immune response characterized by type 2 cytokine production (interleukin [IL]-4, IL-5, and IL-13), pulmonary eosinophilia, increased airway resistance, and severe lung pathology is associated with uncontrolled growth of C. neoformans in the lungs.23Chen GH McNamara DA Hernandez Y Huffnagle GB Toews GB Olszewski MA Inheritance of immune polarization patterns is linked to resistance versus susceptibility to Cryptococcus neoformans in a mouse model.Infect Immun. 2008; 76: 2379-2391Crossref PubMed Scopus (71) Google Scholar, 24Decken K Kohler G Palmer-Lehmann K Wunderlin A Mattner F Magram J Gately MK Alber G Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.Infect Immun. 1998; 66: 4994-5000Crossref PubMed Google Scholar, 26Traynor TR Kuziel WA Toews GB Huffnagle GB CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection.J Immunol. 2000; 164: 2021-2027PubMed Google Scholar, 27Kawakami K Hossain Qureshi M Zhang T Koguchi Y Xie Q Kurimoto M Saito A Interleukin-4 weakens host resistance to pulmonary and disseminated cryptococcal infection caused by combined treatment with interferon-gamma-inducing cytokines.Cell Immunol. 1999; 197: 55-61Crossref PubMed Scopus (43) Google Scholar, 28Olszewski MA Huffnagle GB McDonald RA Lindell DM Moore BB Cook DN Toews GB The role of macrophage inflammatory protein-1alpha/CCL3 in regulation of T cell-mediated immunity to Cryptococcus neoformans infection.J Immunol. 2000; 165: 6429-6436Crossref PubMed Scopus (78) Google Scholar, 29Hernandez Y Arora S Erb-Downward JR McDonald RA Toews GB Huffnagle GB Distinct roles for IL-4 and IL-10 in regulating T2 immunity during allergic bronchopulmonary mycosis.J Immunol. 2005; 174: 1027-1036PubMed Google Scholar, 30Jain AV Zhang Y Fields WB McNamara DA Choe MY Chen GH Erb-Downward J Osterholzer JJ Toews GB Huffnagle GB Olszewski MA Th2 but not Th1 immune bias results in altered lung functions in a murine model of pulmonary Cryptococcus neoformans infection.Infect Immun. 2009; 77: 5389-5399Crossref PubMed Scopus (71) Google Scholar The final link in anticryptococcal host defense is classical activation of macrophages (CAM) that can occur as a consequence of Th1-derived signals.23Chen GH McNamara DA Hernandez Y Huffnagle GB Toews GB Olszewski MA Inheritance of immune polarization patterns is linked to resistance versus susceptibility to Cryptococcus neoformans in a mouse model.Infect Immun. 2008; 76: 2379-2391Crossref PubMed Scopus (71) Google Scholar, 30Jain AV Zhang Y Fields WB McNamara DA Choe MY Chen GH Erb-Downward J Osterholzer JJ Toews GB Huffnagle GB Olszewski MA Th2 but not Th1 immune bias results in altered lung functions in a murine model of pulmonary Cryptococcus neoformans infection.Infect Immun. 2009; 77: 5389-5399Crossref PubMed Scopus (71) Google Scholar, 31Hardison S Ravi S Wozniak K Young M Olszewski M Wormley F Pulmonary infection with an interferon-gamma producing cryptococcus neoformans strain results in classical macrophage activation and protection.Am J Pathol. 2010; 176: 774-785Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 32Zhang Y Wang F Tompkins KC McNamara A Jain AV Moore BB Toews GB Huffnagle GB Olszewski MA Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99.Am J Pathol. 2009; 175: 2489-2500Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar CAM are thought to be the major effector cells that can effectively destroy cryptococci. In contrast, alternatively activated macrophages (AAM) harbor C. neoformans.11Arora S Hernandez Y Erb-Downward JR McDonald RA Toews GB Huffnagle GB Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis.J Immunol. 2005; 174: 6346-6356PubMed Google Scholar, 32Zhang Y Wang F Tompkins KC McNamara A Jain AV Moore BB Toews GB Huffnagle GB Olszewski MA Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99.Am J Pathol. 2009; 175: 2489-2500Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 33Muller U Stenzel W Kohler G Werner C Polte T Hansen G Schutze N Straubinger RK Blessing M McKenzie AN Brombacher F Alber G IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans.J Immunol. 2007; 179: 5367-5377PubMed Google Scholar, 34Osterholzer JJ Surana R Milam JE Montano GT Chen GH Sonstein J Curtis JL Huffnagle GB Toews GB Olszewski MA Cryptococcal urease promotes the accumulation of immature dendritic cells and a non-protective T2 immune response within the lung.Am J Pathol. 2009; 174: 932-943Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Generation of CAM/AAM has been postulated to be regulated by Th1/Th2 bias;11Arora S Hernandez Y Erb-Downward JR McDonald RA Toews GB Huffnagle GB Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis.J Immunol. 2005; 174: 6346-6356PubMed Google Scholar, 22Chen GH McDonald RA Wells JC Huffnagle GB Lukacs NW Toews GB The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans.Infect Immun. 2005; 73: 1788-1796Crossref PubMed Scopus (70) Google Scholar, 23Chen GH McNamara DA Hernandez Y Huffnagle GB Toews GB Olszewski MA Inheritance of immune polarization patterns is linked to resistance versus susceptibility to Cryptococcus neoformans in a mouse model.Infect Immun. 2008; 76: 2379-2391Crossref PubMed Scopus (71) Google Scholar, 30Jain AV Zhang Y Fields WB McNamara DA Choe MY Chen GH Erb-Downward J Osterholzer JJ Toews GB Huffnagle GB Olszewski MA Th2 but not Th1 immune bias results in altered lung functions in a murine model of pulmonary Cryptococcus neoformans infection.Infect Immun. 2009; 77: 5389-5399Crossref PubMed Scopus (71) Google Scholar, 33Muller U Stenzel W Kohler G Werner C Polte T Hansen G Schutze N Straubinger RK Blessing M McKenzie AN Brombacher F Alber G IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans.J Immunol. 2007; 179: 5367-5377PubMed Google Scholar, 35Muller U Stenzel W Kohler G Polte T Blessing M Mann A Piehler D Brombacher F Alber G A gene-dosage effect for interleukin-4 receptor alpha-chain expression has an impact on Th2-mediated allergic inflammation during bronchopulmonary mycosis.J Infect Dis. 2008; 198: 1714-1721Crossref PubMed Scopus (25) Google Scholar however, differential activation of macrophages can also occur in response to other factors, such as stimulation of toll-like receptors (TLRs) by microbial products.36El Kasmi KC Qualls JE Pesce JT Smith AM Thompson RW Henao-Tamayo M Basaraba RJ Konig T Schleicher U Koo MS Kaplan G Fitzgerald KA Tuomanen EI Orme IM Kanneganti TD Bogdan C Wynn TA Murray PJ Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens.Nat Immunol. 2008; 9: 1399-1406Crossref PubMed Scopus (476) Google Scholar, 37Martinez FO Sica A Mantovani A Locati M Macrophage activation and polarization.Front Biosci. 2008; 13: 453-461Crossref PubMed Scopus (2275) Google Scholar TLRs have been found to be critical for immune recognition and clearance of viral, bacterial, protozoan, and fungal pathogens.38Babu S Bhat SQ Kumar NP Anuradha R Kumaran P Gopi PG Kolappan C Kumaraswami V Nutman TB Attenuation of toll-like receptor expression and function in latent tuberculosis by coexistent filarial infection with restoration following antifilarial chemotherapy.PLoS Negl Trop Dis. 2009; 3: e489Crossref PubMed Scopus (45) Google Scholar, 39Krutzik SR Tan B Li H Ochoa MT Liu PT Sharfstein SE Graeber TG Sieling PA Liu YJ Rea TH Bloom BR Modlin RL TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells.Nat Med. 2005; 11: 653-660Crossref PubMed Scopus (333) Google Scholar, 40Mun HS Aosai F Norose K Chen M Piao LX Takeuchi O Akira S Ishikura H Yano A TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection.Int Immunol. 2003; 15: 1081-1087Crossref PubMed Scopus (168) Google Scholar, 41Abou Fakher FH Rachinel N Klimczak M Louis J Doyen N TLR9-dependent activation of dendritic cells by DNA from Leishmania major favors Th1 cell development and the resolution of lesions.J Immunol. 2009; 182: 1386-1396PubMed Google Scholar The role of TLRs in anticryptococcal host defenses is not fully understood. While TLR2 and TLR4 have been shown to respond to C. neoformans products,42Yauch LE Mansour MK Levitz SM Receptor-mediated clearance of Cryptococcus neoformans capsular polysaccharide in vivo.Infect Immun. 2005; 73: 8429-8432Crossref PubMed Scopus (34) Google Scholar, 43Shoham S Huang C Chen JM Golenbock DT Levitz SM Toll-like receptor 4 mediates intracellular signaling without TNF-alpha release in response to Cryptococcus neoformans polysaccharide capsule.J Immunol. 2001; 166: 4620-4626PubMed Google Scholar their in vivo effects are minimal or highly inconsistent between different studies.44Biondo C Midiri A Messina L Tomasello F Garufi G Catania MR Bombaci M Beninati C Teti G Mancuso G MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans.Eur J Immunol. 2005; 35: 870-878Crossref PubMed Scopus (114) Google Scholar, 45Nakamura K Miyagi K Koguchi Y Kinjo Y Uezu K Kinjo T Akamine M Fujita J Kawamura I Mitsuyama M Adachi Y Ohno N Takeda K Akira S Miyazato A Kaku M Kawakami K Limited contribution of Toll-like receptor 2 and 4 to the host response to a fungal infectious pathogen, Cryptococcus neoformans.FEMS Immunol Med Microbiol. 2006; 47: 148-154Crossref PubMed Scopus (68) Google Scholar TLR9 is a member of the TLR family located intracellularly in the cytoplasm and binding to cytoplasmic endosomes of dendritic cells (DC), macrophages, and other cells of the immune system.46Wagner H The immunobiology of the TLR9 subfamily.Trends in Immunology. 2004; 25: 381-386Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar TLR9 coupling/signaling occurs presumably after the microbe becomes ingested and lysed within the endosome, exposing the CpG DNA (TLR9 ligand).47Krieg AM CpG motifs: the active ingredient in bacterial extracts?.Nat Med. 2003; 9: 831-835Crossref PubMed Scopus (252) Google Scholar Stimulation of TLR9 with microbial or synthetic CpGDNA enhances DC maturation and facilitates Th1 driving IL-12 production by these cells.36El Kasmi KC Qualls JE Pesce JT Smith AM Thompson RW Henao-Tamayo M Basaraba RJ Konig T Schleicher U Koo MS Kaplan G Fitzgerald KA Tuomanen EI Orme IM Kanneganti TD Bogdan C Wynn TA Murray PJ Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens.Nat Immunol. 2008; 9: 1399-1406Crossref PubMed Scopus (476) Google Scholar, 41Abou Fakher FH Rachinel N Klimczak M Louis J Doyen N TLR9-dependent activation of dendritic cells by DNA from Leishmania major favors Th1 cell development and the resolution of lesions.J Immunol. 2009; 182: 1386-1396PubMed Google Scholar, 48Bhan U Trujillo G Lyn-Kew K Newstead MW Zeng X Hogaboam CM Krieg AM Standiford TJ Toll-like receptor 9 regulates the lung macrophage phenotype and host immunity in murine pneumonia caused by Legionella pneumophila.Infect Immun. 2008; 76: 2895-2904Crossref PubMed Scopus (66) Google Scholar, 49Bhan U Lukacs NW Osterholzer JJ Newstead MW Zeng X Moore TA McMillan TR Krieg AM Akira S Standiford TJ TLR9 is required for protective innate immunity in Gram-negative bacterial pneumonia: role of dendritic cells.J Immunol. 2007; 179: 3937-3946PubMed Google Scholar, 50Miyazato A Nakamura K Yamamoto N Mora-Montes HM Tanaka M Abe Y Tanno D Inden K Gang X Ishii K Takeda K Akira S Saijo S Iwakura Y Adachi Y Ohno N Mitsutake K Gow NA Kaku M Kawakami K Toll-like receptor 9-dependent activation of myeloid dendritic cells by deoxynucleic acids from Candida albicans.Infect Immun. 2009; 77: 3056-3064Crossref PubMed Scopus (84) Google Scholar, 51Zaks K Jordan M Guth A Sellins K Kedl R Izzo A Bosio C Dow S Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes.J Immunol. 2006; 176: 7335-7345PubMed Google Scholar Thus, TLR9 activation is thought to promote Th1 skewing and prevent Th2 skewing during the development of the adaptive immune responses. Previous studies indicated that TLR9 contributes to anticryptococcal host defenses.52Nakamura K Miyazato A Xiao G Hatta M Inden K Aoyagi T Shiratori K Takeda K Akira S Saijo S Iwakura Y Adachi Y Ohno N Suzuki K Fujita J Kaku M Kawakami K Deoxynucleic acids from Cryptococcus neoformans activate myeloid dendritic cells via a TLR9-dependent pathway.J Immunol. 2008; 180: 4067-4074PubMed Google Scholar, 53Dan JM Wang JP Lee CK Levitz SM Cooperative stimulation of dendritic cells by Cryptococcus neoformans mannoproteins and CpG oligodeoxynucleotides.PLoS One. 2008; 3: e2046Crossref PubMed Scopus (52) Google Scholar, 54Edwards L Williams AE Krieg AM Rae AJ Snelgrove RJ Hussell T Stimulation via Toll-like receptor 9 reduces Cryptococcus neoformans-induced pulmonary inflammation in an IL-12-dependent manner.Eur J Immunol. 2005; 35: 273-281Crossref PubMed Scopus (47) Google Scholar Synthetic CpGDNA co-administered during C. neoformans infection enhances the development of Th1 response and reduces C. neoformans burden.54Edwards L Williams AE Krieg AM Rae AJ Snelgrove RJ Hussell T Stimulation via Toll-like receptor 9 reduces Cryptococcus neoformans-induced pulmonary inflammation in an IL-12-dependent manner.Eur J Immunol. 2005; 35: 273-281Crossref PubMed Scopus (47) Google Scholar In addition, cooperative stimulation of DC by cryptococcal mannoproteins and CpG OligodN was demonstrated in vitro.53Dan JM Wang JP Lee CK Levitz SM Cooperative stimulation of dendritic cells by Cryptococcus neoformans mannoproteins and CpG oligodeoxynucleotides.PLoS One. 2008; 3: e2046Crossref PubMed Scopus (52) Google Scholar Cryptococcal DNA and cell lysates have been shown to activate dendritic cell maturation and to induce IL-12 (pro-Th1 cytokine) production via TLR9 mediated mechanism in vitro.52Nakamura K Miyazato A Xiao G Hatta M Inden K Aoyagi T Shiratori K Takeda K Akira S Saijo S Iwakura Y Adachi Y Ohno N Suzuki K Fujita J Kaku M Kawakami K Deoxynucleic acids from Cryptococcus neoformans activate myeloid dendritic cells via a TLR9-dependent pathway.J Immunol. 2008; 180: 4067-4074PubMed Google Scholar Furthermore, TLR9 contributes to the rapid/innate clearance of an acapsular mutant Cap67 in vivo.52Nakamura K Miyazato A Xiao G Hatta M Inden K Aoyagi T Shiratori K Takeda K Akira S Saijo S Iwakura Y Adachi Y Ohno N Suzuki K Fujita J Kaku M Kawakami K Deoxynucleic acids from Cryptococcus neoformans activate myeloid dendritic cells via a TLR9-dependent pathway.J Immunol. 2008; 180: 4067-4074PubMed Google Scholar It remains unknown if TLR9 is required for the development of natural adaptive immunity to C. neoformans and if it would be required for clearance of clinically relevant (encapsulated) organisms. In the present study, we investigate the role of TLR9 on pulmonary clearance of strain 52D (24067, an encapsulated clinical isolate) and its effects on the effector adaptive immune mechanisms: 1) pulmonary lymphocyte accumulation, 2) immune polarization, and 3) recruitment/activation of macrophages. This is the first report to establish the requirement of TLR9 signaling for the development of adaptive anticryptococcal immunity and clearance of the encapsulated organism from the infected lungs. Female wild-type BALB/c mice were obtained from Jackson Laboratories (Bar Harbor, ME). TLR9−/− mice were bred at the University of Michigan/Ann Arbor Veterans Affairs Medical Center using micro-isolator cages covered with a filter top, with food/water provided ad libitum. Mice were aged to 8 to 10 weeks at the time of infection. At the time of data collection, mice were humanely euthanized by CO2 inhalation. All experiments were approved by the University Committee on the Use and Care of Animals and the Veterans Affairs Institutional Animal Care and Use Committee. C. neoformans strain 52D (ATCC 24067) was recovered from 10% glycerol frozen stocks stored at −80°C and grown to stationary phase at 36°C in Sabouraud dextrose broth (1% neopeptone, 2% dextrose; Difco, Detroit, MI) on a shaker. The cultures were then washed in nonpyrogenic saline (Travenol, Deerfield, IL), counted on a hemocytometer, and diluted to 3.3 × 105 yeast cells/ml in sterile nonpyrogenic saline. Mice were anesthetized via intraperitoneal injection of ketamine/xylazine (ketamine/xylazine 100/6.8 mg/kg/body weight) and were restrained on a foam plate. A small incision was made through the skin covering the trachea. The underlying salivary glands and muscles were separated. Infection was performed by intratracheal injection of 30 μl (104 colony forming units [CFU]) via 30-gauge needle actuated from a 1 ml tuberculin syringe with C. neoformans suspension (3.3 × 105/ml). After inoculation, the skin was closed with cyanoacrylate adhesive, and the mice were monitored during recovery from the anesthesia. For determination of microbial burden in the lungs, small aliquots of dispersed lungs were collected following the digest procedure. For determination of spleen and brain CFU, the spleens and brains were dissected using sterile instruments, placed in 2 ml of sterile water and homogenized. Series of 10-fold dilutions of the lung, spleen, and brain samples were plated on Sabouraud dextrose agar plates in duplicates in 10 μl aliquots and incubated at room temperature. C. neoformans colonies were counted 2 days later and the number of CFU was calculated on a per-organ base. The lungs from each mouse were excised, washed in RPMI, minced with scissors, and digested enzymatically at 37°C for 30 minutes in 15 ml/mouse of digestion buffer [RPMI, 5% fetal bovine serum, penicillin, and streptomycin (all from Invitrogen, Grand Island, NY); 1 mg/ml Collagenase A (Roche Diagnostics, Indianapolis, IN); and 30 μg/ml DNase (Sigma, St. Louis, MO)] and processed as previously described.28Olszewski MA Huffnagle GB McDonald RA Lindell DM Moore BB Cook DN Toews GB The role of macrophage inflammatory protein-1alpha/CCL3 in regulation of T cell-mediated immunity to Cryptococcus neoformans infection.J Immunol. 2000; 165: 6429-6436Crossref PubMed Scopus (78) Google Scholar, 55Olszewski MA Huffnagle GB Traynor TR McDonald RA Cook DN Toews GB Regulatory effects of macrophage inflammatory protein 1alpha/CCL3 on the development of immunity to Cryptococcus neoformans depend on expression of early inflammatory cytokines.Infect Immun. 2001; 69: 6256-6263Crossref PubMed Scopus (43) Google Scholar The cell suspension and tissue fragments were further dispersed by repeated aspiration" @default.
• W1987746874 created "2016-06-24" @default.
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• W1987746874 date "2010-08-01" @default.
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• W1987746874 title "TLR9 Signaling Is Required for Generation of the Adaptive Immune Protection in Cryptococcus neoformans-Infected Lungs" @default.
• W1987746874 cites W114620590 @default.
• W1987746874 cites W1486259351 @default.
• W1987746874 cites W1539825474 @default.
• W1987746874 cites W1542277406 @default.
• W1987746874 cites W1552384509 @default.
• W1987746874 cites W1635217668 @default.
• W1987746874 cites W1733554212 @default.
• W1987746874 cites W1887755235 @default.
• W1987746874 cites W1896668130 @default.
• W1987746874 cites W1902864294 @default.
• W1987746874 cites W1912169188 @default.
• W1987746874 cites W1929903403 @default.
• W1987746874 cites W1962910304 @default.
• W1987746874 cites W1970511844 @default.
• W1987746874 cites W1975088467 @default.
• W1987746874 cites W1977635065 @default.
• W1987746874 cites W1988604605 @default.
• W1987746874 cites W1998820252 @default.
• W1987746874 cites W2007157395 @default.
• W1987746874 cites W2007373071 @default.
• W1987746874 cites W2016479626 @default.
• W1987746874 cites W2018367888 @default.
• W1987746874 cites W2020744745 @default.
• W1987746874 cites W2023309048 @default.
• W1987746874 cites W2024248233 @default.
• W1987746874 cites W2025994596 @default.
• W1987746874 cites W2031528938 @default.
• W1987746874 cites W2032354959 @default.
• W1987746874 cites W2038461328 @default.
• W1987746874 cites W2040386323 @default.
• W1987746874 cites W2050436579 @default.
• W1987746874 cites W2050497805 @default.
• W1987746874 cites W2052931063 @default.
• W1987746874 cites W2055283107 @default.
• W1987746874 cites W2070541423 @default.
• W1987746874 cites W2073151343 @default.
• W1987746874 cites W2075686934 @default.
• W1987746874 cites W2081015097 @default.
• W1987746874 cites W2082736230 @default.
• W1987746874 cites W2093151008 @default.
• W1987746874 cites W2097858152 @default.
• W1987746874 cites W2099568670 @default.
• W1987746874 cites W2100488509 @default.
• W1987746874 cites W2104281761 @default.
• W1987746874 cites W2104833477 @default.
• W1987746874 cites W2108445337 @default.
• W1987746874 cites W2109528296 @default.
• W1987746874 cites W2112853487 @default.
• W1987746874 cites W2112960660 @default.
• W1987746874 cites W2115831480 @default.
• W1987746874 cites W2119182059 @default.
• W1987746874 cites W2122664093 @default.
• W1987746874 cites W2124655157 @default.
• W1987746874 cites W2125317283 @default.
• W1987746874 cites W2126694864 @default.
• W1987746874 cites W2127145634 @default.
• W1987746874 cites W2130652971 @default.
• W1987746874 cites W2135597173 @default.
• W1987746874 cites W2136583839 @default.
• W1987746874 cites W2137640965 @default.
• W1987746874 cites W2139604805 @default.
• W1987746874 cites W2146171603 @default.
• W1987746874 cites W2151045435 @default.
• W1987746874 cites W2151261534 @default.
• W1987746874 cites W2153040975 @default.
• W1987746874 cites W2159943906 @default.
• W1987746874 cites W2161052986 @default.
• W1987746874 cites W2162742103 @default.
• W1987746874 cites W2167916571 @default.
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