Abstract
Aflatoxins are mycotoxins secreted by Aspergillus flavus, which can colonize the respiratory tract and cause fungal rhinosinusitis or bronchopulmonary aspergillosis. A. flavus is the second leading cause of invasive aspergillosis worldwide. Because many respiratory pathogens secrete toxins to impair mucociliary immunity, we examined the effects of acute exposure to aflatoxins on airway cell physiology. Using air-liquid interface cultures of primary human sinonasal and bronchial cells, we imaged ciliary beat frequency (CBF), intracellular calcium, and nitric oxide (NO). Exposure to aflatoxins (0.1 to 10 μM; 5 to 10 minutes) reduced baseline (~6–12%) and agonist-stimulated CBF. Conditioned media (CM) from A. fumigatus, A. niger, and A. flavus cultures also reduced CBF by ~10% after 60 min exposure, but effects were blocked by an anti-aflatoxin antibody only with A. flavus CM. CBF reduction required protein kinase C but was not associated with changes in calcium or NO. However, AFB2 reduced NO production by ~50% during stimulation of the ciliary-localized T2R38 receptor. Using a fluorescent reporter construct expressed in A549 cells, we directly observed activation of PKC activity by AFB2. Aflatoxins secreted by respiratory A. flavus may impair motile and chemosensory functions of airway cilia, contributing to pathogenesis of fungal airway diseases.
Highlights
Mucociliary clearance (MCC) is the primary physical defense of the respiratory tract against inhaled pathogens[1]
Because protein kinase C (PKC) can decrease CBF32,33 through phosphorylation of ciliary proteins[32,33], we hypothesized that aflatoxins may have acute effects on MCC that contribute to A. flavus pathogenesis
No additive effects of aflatoxin B2 (AFB2) were observed when sinonasal air-liquid interface cultures (ALIs) were pretreated with the phorbol ester phorbol-12-myristate-13-acetate (PMA), nor was ciliary beat frequency (CBF) further reduced when PMA was added to ALIs pre-treated with AFB2 (Fig. 1h), supporting the hypothesis that AFB2 reduces CBF through a PKC-dependent pathway
Summary
Mucociliary clearance (MCC) is the primary physical defense of the respiratory tract against inhaled pathogens[1]. Upper respiratory infections (URIs) often result in chronic rhinosinusitis (CRS), a complex syndrome involving stasis of sinonasal secretions and inflammation. While ~90% of Aspergillus are non-pathogenic, some are opportunistic pathogens that colonize the human respiratory tract[9,10], including A. fumigatus, A. niger, and A. flavus. Sensitization to colonizing Aspergillus can cause allergic bronchopulmonary aspergillosis[11] or allergic fungal rhinosinusitis[12]. It is critical to understand the interactions of Aspergillus with the airway epithelium to understand the pathogenesis of fungal respiratory infections. Pathogenic Aspergillus, A. flavus is the second-leading cause of invasive aspergillosis[20,21]. Because PKC can decrease CBF32,33 through phosphorylation of ciliary proteins[32,33], we hypothesized that aflatoxins may have acute effects on MCC that contribute to A. flavus pathogenesis
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