Immunity to fungi in the lung

Abstract

The respiratory tree maintains sterilizing immunity against human fungal pathogens. Humans inhale ubiquitous filamentous molds and geographically restricted dimorphic fungal pathogens that form small airborne conidia. In addition, pathogenic yeasts, exemplified by encapsulated Cryptococcus species, and Pneumocystis pose significant fungal threats to the lung. Classically, fungal pneumonia occurs in immune compromised individuals, specifically in patients with HIV/AIDS, in patients with hematologic malignancies, in organ transplant recipients, and in patients treated with corticosteroids and targeted biologics that impair fungal immune surveillance in the lung. The emergence of fungal co-infections during severe influenza and COVID-19 underscores the impairment of fungus-specific host defense pathways in the lung by respiratory viruses and by medical therapies to treat viral infections. Beyond life-threatening invasive syndromes, fungal antigen exposure can exacerbate allergenic disease in the lung. In this review, we discuss emerging principles of lung-specific antifungal immunity, integrate the contributions and cooperation of lung epithelial, innate immune, and adaptive immune cells to mucosal barrier immunity, and highlight the pathogenesis of fungal-associated allergenic disease. Improved understanding of fungus-specific immunity in the respiratory tree has paved the way to develop improved diagnostic, pre-emptive, therapeutic, and vaccine approaches for fungal diseases of the lung.

Keywords: Aspergillus; Blastomyces; Cryptococcus; Fungus; Histoplasma; Immunity; Infection; Innate; Lung; Lymphocyte; Macrophage; Monocyte; Mucomycosis; Mucorales; Mycosis; Neutrophil; Paracoccidioides; Pneumonia; T cell; Talaromyces.

Fig. 1.

Anatomy of the respiratory tract and lung. A. The vocal cords in the human respiratory tract form the boundary between the upper and lower respiratory tracts. Proximal airways function largely to conduct air to the distal airways. Distal airways are comprised of the respiratory bronchioles, alveolar ducts, and alveoli where gas exchange occurs. The inset depicts the epithelial architecture of the trachea and bronchi (upper panel) as well as the bronchioles (lower panel). PNEC, pulmonary neuroendocrine cell. B. The schematic depicts the cellular architecture of alveoli that includes type I and type II alveolar epithelial cells (AEC), alveolar macrophages, surfactant, and lung-resident dendritic cells. Gas exchange occurs via adjacent capillaries.

Fig. 2.

Immune crosstalk is a central feature of pulmonary antifungal immunity. A. Aspergillus conidia induce the rapid release of IL-1 α/β by lung-resident AMs and DCs. This process activates IL-1R/MyD88 signaling in pulmonary epithelial cells which causes the release of neutrophil chemoattractants, primarily CXCL1 and CXCL5. CXC- chemokines collaborate with LTB_4, C5a, and galectin-3 to mediate neutrophil influx to infected airways. CCL2, –7, and –12 mediate the ensuing influx of CCR2⁺ monocytes into the lung parenchyma. Neutrophils, monocytes, and monocyte-derived dendritic cells (Mo-DCs) engulf conidia into phagolysosomes and inactivate fungal cells via products of NADPH oxidase. Monocyte-regulated type I and type III IFNs enhance fungal killing. Fungus-engaged neutrophils and Mo-DCs release CXCL9 and CXCL10 which recruits CXCR3⁺ plasmacytoid DCs from the circulation into the lung. Plasmacytoid DCs (pDC) do not bind conidia but enhance the oxidative burst to boost conidial killing in neutrophils. GM-CSF enhances this process as well. B. During Blastomyces infection, early IL-1α/β release triggers epithelial CCL20 production which acts on CCR6⁺ ILCs and mediates their trafficking to the infected lung. ILCs and natural T helper 17 cells produce IL-17 and GM-CSF which potentiate yeast cell killing by neutrophils and Mo-DCs.

Fig. 3.

Fungal proteases and candidalysin can initiate allergenic inflammation. A fungal protease cleaves IL-33 and disrupts epithelial junctions. Processed IL-33 penetrates the barrier into the lung parenchyma, binds to ST2 receptors on type 2 innate lymphoid cells (ILC2), and drives the production of IL-5 by ILC2. This process drives eosinophil recruitment. Protease injury to the epithelial cell junctions also activates TRPV4 and causes calcium to flux into epithelial cells. Calcium signals through calcineurin and promotes CCL2 release from epithelial cells, resulting in the recruitment of Mo-DCs. Mo-DCs present antigen to T helper 2 cells in the lungs that secrete IL-5 and coordinate eosinophil influx and allergenic disease. Candidalysin, a peptide toxin released by Candida albicans, can damage lung epithelial cells in the upper airway. Platelets that arrive to limit hemorrhage interact with candidalysin, release dickkopf-1 (Dkk-1), and Dkk-1 promotes T helper 2-and T helper 17-dependent allergic responses.