title: Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection.
abstract: We investigated mechanisms by which TLR9 signaling promoted the development of the protective response to Cryptococcus neoformans in mice with cryptococcal pneumonia. The afferent (week 1) and efferent (week 3) phase immune parameters were analyzed in the infected wild-type (TLR9(+/+)) and TLR-deficient (TLR9(-/-)) mice. TLR9 deletion diminished 1) accumulation and activation of CD11b(+) dendritic cells (DCs), 2) the induction of IFN-γ and CCR2 chemokines CCL7, CCL12, but not CCL2, at week 1, and 3) pulmonary accumulation and activation of the major effector cells CD4(+) and CD8(+) T cells, CD11b(+) lung DCs, and exudate macrophages at week 3. The significance of CCL7 induction downstream of TLR9 signaling was investigated by determining whether CCL7 reconstitution would improve immunological parameters in C. neoformans-infected TLR9(-/-) mice. Early reconstitution with CCL7 1) improved accumulation and activation of CD11b(+) DCs at week 1, 2) restored early IFN-γ production in the lungs, and 3) restored the accumulation of major effector cell subsets. CCL7 administration abolished the difference in lung fungal burdens between TLR9(+/+) and TLR9(-/-) mice at week 3; however, significant reduction of fungal burdens between PBS- and CCL7-treated mice has not been observed, suggesting that additional mechanism(s) apart from early CCL7 induction contribute to optimal fungal clearance in TLR9(+/+) mice. Collectively, we show that TLR9 signaling during the afferent phase contributes to the development of protective immunity by promoting the early induction of CCL7 and IFN-γ and the subsequent early recruitment and activation of DCs and additional effector cells in mice with cryptococcal pneumonia.
authors.affiliation: Department of Research Service, Veterans Administration Ann Arbor Health System, Ann Arbor, MI 48105, USA.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Qiu
authors.forename: Stuart
authors.initials: S
authors.lastname: Zeltzer
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fuyuan
authors.initials: F
authors.lastname: Wang
authors.forename: Gwo-Hsiao
authors.initials: GH
authors.lastname: Chen
authors.forename: Jeremy
authors.initials: J
authors.lastname: Dayrit
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Murdock
authors.forename: Urvashi
authors.initials: U
authors.lastname: Bhan
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D054410:Chemokine CCL7 / Q000276:immunology*; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D003455:Cryptococcus neoformans; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000276:immunology; D011014:Pneumonia / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D039481:CD11b Antigen; C491224:Ccl12 protein, mouse; D054410:Chemokine CCL7; D018945:Monocyte Chemoattractant Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma