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MDA5 signaling induces type 1 IFN- and IL-1-dependent lung vascular permeability which protects mice from opportunistic fungal infection.
Front Immunol. 2022; 13:931194.FI

Abstract

Lungs balance threat from primary viral infection, secondary infection, and inflammatory damage. Severe pulmonary inflammation induces vascular permeability, edema, and organ dysfunction. We previously demonstrated that poly(I:C) (pICLC) induced type 1 interferon (t1IFN) protected mice from Cryptococcus gattii (Cg) via local iron restriction. Here we show pICLC increased serum protein and intravenously injected FITC-dextran in the lung airspace suggesting pICLC induces vascular permeability. Interestingly, pICLC induced a pro-inflammatory signature with significant expression of IL-1 and IL-6 which depended on MDA5 and t1IFN. Vascular permeability depended on MDA5, t1IFN, IL-1, and IL-6. T1IFN also induced MDA5 and other MDA5 signaling components suggesting that positive feedback contributes to t1IFN dependent expression of the pro-inflammatory signature. Vascular permeability, induced by pICLC or another compound, inhibited Cg by limiting iron. These data suggest that pICLC induces t1IFN which potentiates pICLC-MDA5 signaling increasing IL-1 and IL-6 resulting in leakage of antimicrobial serum factors into lung airspace. Thus, induced vascular permeability may act as an innate defense mechanism against opportunistic fungal infection, such as cryptococcosis, and may be exploited as a host-directed therapeutic target.

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Authors+Show Affiliations

Davis MJ
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Martin RE
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Pinheiro GM
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Hoke ES
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Moyer S
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Mayer-Barber KD
Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Chang YC
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.
Kwon-Chung KJ
Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.

MeSH

AnimalsCapillary PermeabilityCryptococcosisCryptococcus gattiiInterferon Type IInterleukin-1Interleukin-6IronLungMiceOpportunistic Infections

Pub Type(s)

Journal Article

Language

eng

PubMed ID

35967332

Citation

Davis, Michael J., et al. "MDA5 Signaling Induces Type 1 IFN- and IL-1-dependent Lung Vascular Permeability Which Protects Mice From Opportunistic Fungal Infection." Frontiers in Immunology, vol. 13, 2022, p. 931194.
Davis MJ, Martin RE, Pinheiro GM, et al. MDA5 signaling induces type 1 IFN- and IL-1-dependent lung vascular permeability which protects mice from opportunistic fungal infection. Front Immunol. 2022;13:931194.
Davis, M. J., Martin, R. E., Pinheiro, G. M., Hoke, E. S., Moyer, S., Mayer-Barber, K. D., Chang, Y. C., & Kwon-Chung, K. J. (2022). MDA5 signaling induces type 1 IFN- and IL-1-dependent lung vascular permeability which protects mice from opportunistic fungal infection. Frontiers in Immunology, 13, 931194. https://doi.org/10.3389/fimmu.2022.931194
Davis MJ, et al. MDA5 Signaling Induces Type 1 IFN- and IL-1-dependent Lung Vascular Permeability Which Protects Mice From Opportunistic Fungal Infection. Front Immunol. 2022;13:931194. PubMed PMID: 35967332.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MDA5 signaling induces type 1 IFN- and IL-1-dependent lung vascular permeability which protects mice from opportunistic fungal infection. AU - Davis,Michael J, AU - Martin,Rachel E, AU - Pinheiro,Giovana M, AU - Hoke,Elizabeth S, AU - Moyer,Shannon, AU - Mayer-Barber,Katrin D, AU - Chang,Yun C, AU - Kwon-Chung,Kyung J, Y1 - 2022/07/28/ PY - 2022/04/28/received PY - 2022/06/29/accepted PY - 2022/8/15/entrez PY - 2022/8/16/pubmed PY - 2022/8/17/medline KW - Cryptococcus KW - IL-1 KW - edema KW - inflammation KW - interferon KW - lungs SP - 931194 EP - 931194 JF - Frontiers in immunology JO - Front Immunol VL - 13 N2 - Lungs balance threat from primary viral infection, secondary infection, and inflammatory damage. Severe pulmonary inflammation induces vascular permeability, edema, and organ dysfunction. We previously demonstrated that poly(I:C) (pICLC) induced type 1 interferon (t1IFN) protected mice from Cryptococcus gattii (Cg) via local iron restriction. Here we show pICLC increased serum protein and intravenously injected FITC-dextran in the lung airspace suggesting pICLC induces vascular permeability. Interestingly, pICLC induced a pro-inflammatory signature with significant expression of IL-1 and IL-6 which depended on MDA5 and t1IFN. Vascular permeability depended on MDA5, t1IFN, IL-1, and IL-6. T1IFN also induced MDA5 and other MDA5 signaling components suggesting that positive feedback contributes to t1IFN dependent expression of the pro-inflammatory signature. Vascular permeability, induced by pICLC or another compound, inhibited Cg by limiting iron. These data suggest that pICLC induces t1IFN which potentiates pICLC-MDA5 signaling increasing IL-1 and IL-6 resulting in leakage of antimicrobial serum factors into lung airspace. Thus, induced vascular permeability may act as an innate defense mechanism against opportunistic fungal infection, such as cryptococcosis, and may be exploited as a host-directed therapeutic target. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/35967332/MDA5_signaling_induces_type_1_IFN__and_IL_1_dependent_lung_vascular_permeability_which_protects_mice_from_opportunistic_fungal_infection_ DB - PRIME DP - Unbound Medicine ER -