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ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/JCI190107

An IFN/STAT1/CYBB Axis Defines Protective Plasmacytoid DC to Neutrophil Crosstalk in Aspergillus fumigatus - Infected mice

Yahui Guo,1 Mariano A. Aufiero,1 Kathleen A.M. Mills,1 Simon A. Grassmann,2 Hyunu Kim,3 Mergim Gjonbalaj,4 Paul Zumbo,5 Audrey Billips,1 Katrina B. Mar,1 Yao Yu,1 Laura Echeverri Tirado,6 Lena Heung,7 Amariliz Rivera,6 Doron Betel,8 Joseph C. Sun,2 and Tobias M. Hohl1

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Guo, Y. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Aufiero, M. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Mills, K. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Grassmann, S. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Kim, H. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Gjonbalaj, M. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Zumbo, P. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Billips, A. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Mar, K. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Yu, Y. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Echeverri Tirado, L. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Heung, L. in: PubMed | Google Scholar |

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Rivera, A. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Betel, D. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Sun, J. in: PubMed | Google Scholar

1Infectious Disease Service, Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

4mmunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, United States of America

5Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America

6Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, United States of America

7Department of Medicine and Department of Biomedical Sciences, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

8Applied Bioinformatics Core, Division of Hematology and Medical Oncology, D, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States of America

Find articles by Hohl, T. in: PubMed | Google Scholar |

Published August 5, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI190107.
Copyright © 2025, Guo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 5, 2025 - Version history
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Abstract

Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung.

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