Sci Transl Med. 2022 Dec 7;14(674):eabq6682. doi: 10.1126/scitranslmed.abq6682. | PubMed

Nicole Sarden^1,2, Sarthak Sinha³, Kyle G Potts⁴, Erwan Pernet^5,6, Carlos H Hiroki^1,2, Mortaza F Hassanabad^1,2, Angela P Nguyen^1,2, Yuefei Lou^1,2, Raquel Farias^1,2, Brent W Winston^1,2, Amy Bromley⁷, Brendan D Snarr⁶, Amanda Z Zucoloto^1,2, Graciela Andonegui¹, Daniel A Muruve¹, Braedon McDonald^1,2, Donald C Sheppard^6,8, Douglas J Mahoney⁴, Maziar Divangahi^5,6, Nicole Rosin³, Jeff Biernaskie³, Bryan G Yipp^1,2

1. Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
2. Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
3. Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada.
4. Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB T2N 4Z6, Canada.
5. Meakins-Christie Laboratories, Departments of Medicine and Pathology, McGill International TB Centre, McGill University, Montreal, QC H4A 3JI, Canada.
6. Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
7. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
8. Division of Infectious Diseases and Department of Medical Microbiology, McGill University Health Centre, Montreal, QC H4A 3JI, Canada.

Abstract

The lung naturally resists Aspergillus fumigatus (Af) in healthy individuals, but multiple conditions can disrupt this resistance, leading to lethal invasive infections. Core processes of natural resistance and its breakdown are undefined. We investigated three distinct conditions predisposing to lethal aspergillosis-severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, influenza A viral pneumonia, and systemic corticosteroid use-in human patients and murine models. We found a conserved and essential coupling of innate B1a lymphocytes, Af-binding natural immunoglobulin G antibodies, and lung neutrophils. Failure of this axis concealed Af from neutrophils, allowing rapid fungal invasion and disease. Reconstituting the axis with immunoglobulin therapy reestablished resistance, thus representing a realistic pathway to repurpose currently available therapies. Together, we report a vital host resistance pathway that is responsible for protecting against life-threatening aspergillosis in the context of distinct susceptibilities.

Presented By Nicole Sarden | ORCID iD