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Sensitivity to allergenic fungi (Alternaria alternata) is associated with acute, severe asthma attacks. Antigen presenting cells (APCs) in the lung sense environmental perturbations that induce cellular stress and metabolic changes and are critical for allergic airway inflammation. However, the mechanisms underlying such environmental sensing by APCs in the lung remains unclear. Here we show that acute Alternaria challenge rapidly induces neutrophil accumulation in airways, and alter expressions of Pyruvate Kinase (PKM2) and hypoxia-inducible factor -1α (Hif-1α) that correlates with proinflammatory mediator release. Blockade of IL33 signaling in vivo led to reduce oxidative stress and glycolysis in lung APCs. Lung-specific ablation of CD11c + cells abrogates Alternaria-induced neutrophil accumulation and inflammation. Furthermore, administration of Alternaria into the airways stimulated APCs and elevate the expression of Glut-1. Mechanistically, we establish that PKM2 is a critical modulator of lung APC activation in Alternaria-induced acute inflammation. Allosteric activation of PKM2 by a small molecule ML265 or siRNA-mediated knock down correlated negatively with glycolysis and activation of APCs. These results collectively demonstrates that PKM2-mediated glycolytic reprogramming by fungal allergen Alternaria influences lung APC activation, thereby promotes acute airway inflammation. Our data support a model in which Alternaria sensitization in airways induce a circuitry of glycolysis and PKM2 regulation that confers an acute activation of APCs in the lung, whose targeting might represent a strategy for asthma treatment., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

We investigated the role of granulocyte macrophage colony-stimulating factor (GM-CSF) in host defense in a murine model of pulmonary cryptococcosis induced by intratracheal inoculation of Cryptococcus neoformans. Pulmonary C. neoformans infection of C57BL/6 mice is an established model of an allergic bronchopulmonary mycosis. Our objective was to determine whether GM-CSF regulates the pulmonary Th2 immune response in C. neoformans-infected C57BL/6 mice. Long-term pulmonary fungistasis was lost in GM-CSF knockout (GM(-/-)) mice, resulting in increased pulmonary burden of fungi between weeks 3 and 5. GM-CSF was required for the early influx of macrophages and CD4 and CD8 T cells into the lungs but was not required later in the infection. Lack of GM-CSF also resulted in reduced eosinophil recruitment and delayed recruitment of mononuclear cells into the airspace. Macrophages from GM(+/+) mice showed numerous hallmarks of alternatively activated macrophages: higher numbers of intracellular cryptococci, YM1 crystals, and induction of CCL17. These hallmarks are absent in macrophages from GM(-/-) mice. Mucus-producing goblet cells were abundantly present within the bronchial epithelial layer in GM(+/+) mice but not in GM(-/-) mice at week 5 after infection. Production of both Th1 and Th2 cytokines was impaired in the absence of GM-CSF, consistent with both reduced C. neoformans clearance and absence of allergic lung pathology.

Allergic fungal sinusitis is a form of noninvasive fungal disease resulting from an IgE-mediated hypersensitivity reaction in atopic individuals. Allergic fungal sinusitis can present with a continuum of symptoms. Accumulation of allergic inspissated mucin may cause simple nasal obstruction or progress to facial deformity with osteolytic destruction and intracranial extension. Multiple species of fungi are now recognized as etiologic factors responsible for initiating the inflammatory response. This article discusses 3 cases involving Aspergillus and Curvularia species, and reviews diagnostic image findings, pathophysiology, and medical-surgical management of this increasingly common disease.

We contend that the presence of concomitant allergic fungal sinusitis (AFS) and allergic bronchopulmonary mycosis in the same patient represents an expression of the same process of fungal hypersensitivity in the upper and lower airways. We have termed this process the SAM syndrome, an acronym for sinobronchial allergic mycosis. Diagnostic criteria have been established for the SAM syndrome, and the clinical characteristics of one previously unreported and four previously reported patients have been tabulated. Patients with the SAM syndrome have chronic sinusitis involving multiple sinuses, asthma, immediate cutaneous reactivity to fungal allergens, peripheral eosinophilia, and radiographic evidence of bronchiectasis. Total serum IgE levels are usually elevated as well. A variety of chest radiographic abnormalities may occur, ranging from mass lesions to diffuse pulmonary infiltrates and even normal findings on chest radiographs. Patients present for an evaluation of either sinus or lung disease and, at that time, demonstrate no clinical features that distinguish them from patients with isolated sinus or lung disease. All patients reported to date have had clinical responses to therapy with corticosteroids. We postulate that SAM is underdiagnosed in patients with AFS, a disease recently reported from medical centers in the southeastern and western United States. Moreover, since our patient had a mutation in the cystic fibrosis transmembrane conductor regulator (CFTR) gene, we further hypothesize that CFTR gene mutations may play an important role in the pathogenesis of the SAM syndrome.

High amounts of fungal spores, bacteria, and bacterial endotoxin have been found in dust associated with the poorly characterized syndrome, organic dust toxic syndrome (ODTS). As part of an ongoing investigation to determine the etiopathogenesis for ODTS, this study has focused on activation of guinea pig bronchial alveolar lavage (BAL) cells as evidenced by the production of superoxide anion in response to fungal spores and lipopolysaccharide (LPS). Fungal spores from Aspergillus candidus, Aspergillus terreus, Aspergillus niger, Aspergillus fumigatus, Eurotima amstelodami, Penicillium spinulosum, and Cladosporium cladosporioides were all shown to increase superoxide anion production, each with different potencies. LPS stimulated little superoxide anion production in BAL cells, but when cells were pretreated with LPS prior to stimulation with fungal spores, superoxide anion production was increased over that induced by either spores or LPS alone. These results suggest that the inhalation of LPS together with fungal spores could possibly provoke abnormal lung pathologies.