During Aspergillus Infection, Monocyte-Derived DCs, Neutrophils, and Plasmacytoid DCs Enhance Innate Immune Defense Through CXCR3-Dependent Crosstalk

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2020 Jun 3

PMID 32485165

Citations 42

Authors

Yahui Guo

Shinji Kasahara

Anupam Jhingran

Nicholas L Tosini

Bing Zhai

Mariano A Aufiero

Kathleen A M Mills

Mergim Gjonbalaj

Vanessa Espinosa

Amariliz Rivera

Andrew D Luster

Tobias M Hohl

Affiliations

Soon will be listed here.

Abstract

Aspergillus fumigatus, a ubiquitous mold, is a common cause of invasive aspergillosis (IA) in immunocompromised patients. Host defense against IA relies on lung-infiltrating neutrophils and monocyte-derived dendritic cells (Mo-DCs). Here, we demonstrate that plasmacytoid dendritic cells (pDCs), which are prototypically antiviral cells, participate in innate immune crosstalk underlying mucosal antifungal immunity. Aspergillus-infected murine Mo-DCs and neutrophils recruited pDCs to the lung by releasing the CXCR3 ligands, CXCL9 and CXCL10, in a Dectin-1 and Card9- and type I and III interferon signaling-dependent manner, respectively. During aspergillosis, circulating pDCs entered the lung in response to CXCR3-dependent signals. Via targeted pDC ablation, we found that pDCs were essential for host defense in the presence of normal neutrophil and Mo-DC numbers. Although interactions between pDC and fungal cells were not detected, pDCs regulated neutrophil NADPH oxidase activity and conidial killing. Thus, pDCs act as positive feedback amplifiers of neutrophil effector activity against inhaled mold conidia.

Citing Articles

Mgl2 cDC2s coordinate fungal allergic airway type 2, but not type 17, inflammation in mice.

Cook P, Brown S, Houlder E, Furlong-Silva J, Conn D, Colombo S Nat Commun. 2025; 16(1):928.

PMID: 39843887 PMC: 11754877. DOI: 10.1038/s41467-024-55663-3.

Advances in Dendritic-Cell-Based Vaccines against Respiratory Fungal Infections.

Kulkarni N, Nanjappa S Vaccines (Basel). 2024; 12(9).

PMID: 39340013 PMC: 11435842. DOI: 10.3390/vaccines12090981.

IFN Receptor 2 Regulates TNF-α-Mediated Damaging Inflammation during Aspergillus Pulmonary Infection.

Rynda-Apple A, Reyes Servin J, Lenz J, Roemer J, Benson E, Hall M J Immunol. 2024; 213(8):1202-1211.

PMID: 39212415 PMC: 11816899. DOI: 10.4049/jimmunol.2200686.

Manipulation of host phagocytosis by fungal pathogens and therapeutic opportunities.

Jia L, Gonzalez K, Orasch T, Schmidt F, Brakhage A Nat Microbiol. 2024; 9(9):2216-2231.

PMID: 39187614 DOI: 10.1038/s41564-024-01780-0.

New developments in Aspergillus fumigatus and host reactive oxygen species responses.

James M, Doss K, Cramer R Curr Opin Microbiol. 2024; 80:102521.

PMID: 39079399 PMC: 11475146. DOI: 10.1016/j.mib.2024.102521.

References

Thapa M, Carr D . CXCR3 deficiency increases susceptibility to genital herpes simplex virus type 2 infection: Uncoupling of CD8+ T-cell effector function but not migration. J Virol. 2009; 83(18):9486-501. PMC: 2738229. DOI: 10.1128/JVI.00854-09. View

Colvin R, Campanella G, Sun J, Luster A . Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function. J Biol Chem. 2004; 279(29):30219-27. DOI: 10.1074/jbc.M403595200. View

Hsu Y, Zhang Y, You Y, Wang D, Li H, Duramad O . The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol. 2006; 8(2):198-205. DOI: 10.1038/ni1426. View

Maldonado S, Fitzgerald-Bocarsly P . Antifungal Activity of Plasmacytoid Dendritic Cells and the Impact of Chronic HIV Infection. Front Immunol. 2017; 8:1705. PMC: 5723005. DOI: 10.3389/fimmu.2017.01705. View

OConnell P, Pepelyayeva Y, Blake M, Hyslop S, Crawford R, Rizzo M . SLAMF7 Is a Critical Negative Regulator of IFN-α-Mediated CXCL10 Production in Chronic HIV Infection. J Immunol. 2018; 202(1):228-238. PMC: 6310109. DOI: 10.4049/jimmunol.1800847. View

Ohmori Y, Wyner L, Narumi S, Armstrong D, STOLER M, Hamilton T . Tumor necrosis factor-alpha induces cell type and tissue-specific expression of chemoattractant cytokines in vivo. Am J Pathol. 1993; 142(3):861-70. PMC: 1886781. View

Sozzani S, Vermi W, Del Prete A, Facchetti F . Trafficking properties of plasmacytoid dendritic cells in health and disease. Trends Immunol. 2010; 31(7):270-7. DOI: 10.1016/j.it.2010.05.004. View

Hirako I, Ataide M, Faustino L, Assis P, Sorensen E, Ueta H . Splenic differentiation and emergence of CCR5CXCL9CXCL10 monocyte-derived dendritic cells in the brain during cerebral malaria. Nat Commun. 2016; 7:13277. PMC: 5097164. DOI: 10.1038/ncomms13277. View

Herbst S, Shah A, Mazon Moya M, Marzola V, Jensen B, Reed A . Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. EMBO Mol Med. 2015; 7(3):240-58. PMC: 4364943. DOI: 10.15252/emmm.201404556. View

10.

Marciano B, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S . Common severe infections in chronic granulomatous disease. Clin Infect Dis. 2014; 60(8):1176-83. PMC: 4400412. DOI: 10.1093/cid/ciu1154. View

11.

Jhingran A, Mar K, Kumasaka D, Knoblaugh S, Ngo L, Segal B . Tracing conidial fate and measuring host cell antifungal activity using a reporter of microbial viability in the lung. Cell Rep. 2012; 2(6):1762-73. PMC: 3712646. DOI: 10.1016/j.celrep.2012.10.026. View

12.

Kohrgruber N, Groger M, Meraner P, Kriehuber E, Petzelbauer P, Brandt S . Plasmacytoid dendritic cell recruitment by immobilized CXCR3 ligands. J Immunol. 2004; 173(11):6592-602. DOI: 10.4049/jimmunol.173.11.6592. View

13.

Serbina N, Pamer E . Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006; 7(3):311-7. DOI: 10.1038/ni1309. View

14.

Swiecki M, Miller H, Sesti-Costa R, Cella M, Gilfillan S, Colonna M . Microbiota induces tonic CCL2 systemic levels that control pDC trafficking in steady state. Mucosal Immunol. 2016; 10(4):936-945. PMC: 5423869. DOI: 10.1038/mi.2016.99. View

15.

Gibrat R, Grouzis J, Rigaud J, Galtier N, Grignon C . Electrostatic analysis of effects of ions on the inhibition of corn root plasma membrane Mg2+-ATPase by the bivalent orthovanadate. Biochim Biophys Acta. 1989; 979(1):46-52. DOI: 10.1016/0005-2736(89)90521-x. View

16.

Mehrad B, Strieter R, Moore T, Tsai W, Lira S, Standiford T . CXC chemokine receptor-2 ligands are necessary components of neutrophil-mediated host defense in invasive pulmonary aspergillosis. J Immunol. 1999; 163(11):6086-94. View

17.

Bonnett C, Cornish E, Harmsen A, Burritt J . Early neutrophil recruitment and aggregation in the murine lung inhibit germination of Aspergillus fumigatus Conidia. Infect Immun. 2006; 74(12):6528-39. PMC: 1698102. DOI: 10.1128/IAI.00909-06. View

18.

Ang D, Oates C, Schuelein R, Kelly M, Sansom F, Bourges D . Cutting edge: pulmonary Legionella pneumophila is controlled by plasmacytoid dendritic cells but not type I IFN. J Immunol. 2010; 184(10):5429-33. DOI: 10.4049/jimmunol.1000128. View

19.

Rogers N, Slack E, Edwards A, Nolte M, Schulz O, Schweighoffer E . Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005; 22(4):507-17. DOI: 10.1016/j.immuni.2005.03.004. View

20.

Saijo S, Fujikado N, Furuta T, Chung S, Kotaki H, Seki K . Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat Immunol. 2006; 8(1):39-46. DOI: 10.1038/ni1425. View