Lung epithelium: barrier immunity to inhaled fungi and driver of fungal-associated allergic asthma
Introduction
For terrestrial vertebrates, the lungs are a primary interface with the external environment. The delicate and moist structures needed for efficient gas exchange between the blood and air also, unfortunately, present a suitable environment for fungal pathogens to invade and cause disease. This vulnerability is partially circumvented by the cavernous, cobbled architecture of the lungs (Figure 1). Particulates must navigate their way through ever winding and constricting passages of the trachea, bronchi, and bronchioles before reaching the fragile site of gas exchange in the terminal alveolar air space. Mucous and cilia lining the airways impose further physical constraints by capturing and reversing the trajectory of inhaled pathogens. Additionally, a heterogeneous assortment of epithelial cell subsets, each with unique functions, are distributed along the airways. Club cells, ciliated columnar cells, basal cells, and pulmonary neuroendocrine cells decorate the proximal airways, whereas type-1 and type-2 alveolar cells populate the distal epithelium. The asymmetric polarization of these epithelial cell subsets also augments their sophisticated behaviors. The apical surfaces of the epithelium expel antimicrobial peptides, mucous, and surfactants into the airway lumen. Conversely, the basolateral surfaces secrete chemotactic factors toward the lung parenchyma, thereby recruiting long ranging leukocytes and initiating the earliest events of immunity. The broad importance of the epithelium as a barrier to microbial invasion is widely recognized. However, the dynamic involvement of epithelial cells and their potent functions in fungal pathogen resistance are only beginning to be understood.
Humans inhale several liters of air every minute, and with each breath, we aspirate numerous fungal yeasts and spores [1]. Ensuing invasive disease is largely determined by the quality and quantity of inhaled fungi, as well as host intrinsic factors like immune status. Primary fungal pathogens (e.g. Blastomyces, Coccidioides, Cryptococcus gattii, and Histoplasma) cause symptomatic disease in otherwise healthy individuals, indicating that exposure is a major determinant of mycosis (Figure 2) [2••]. Infections with other fungi (e.g. Aspergillus fumigatus, Cryptococcus neoformans, and Pneumocystis) commonly arise in people with weakened immune systems [2••]. This suggests that opportunistic fungal pathogens are likely less virulent, yet more prevalent in the environment than primary fungal pathogens (Figure 2). In both cases, the earliest events of frontline defense after fungal exposure occur at the epithelial surfaces. Investigations into the evolutionary rivalry between lung epithelial cells and fungi could spur paradigm-shifting treatments that prevent or cure invasive fungal disease.
Asthma is a lifelong illness noted by periodic episodes of respiratory distress. According to the World Health Organization, asthma affects an estimated 235 million people and is the most common chronic disease in children [3]. The initial sensitization and subsequent recurrence of asthmatic events is often triggered by inhalation of environmental allergens [4]. Therefore, allergic asthma can be operationally defined as an inappropriate response to a normally innocuous extrinsic stimulus. A significant proportion of cases of allergic airway disease are associated with fungal exposure [5, 6, 7, 8]. Household molds, like Aspergillus and Penicillium, as well as the outdoor fungus, Alternaria, account for a majority of these fungal-associated allergies [8]. Inhalation of intact fungi and fungal components triggers allergic responses at the respiratory mucosa. Unlike invasive fungal infections, most evidence to date implicates epithelial cells as having a detrimental impact on lung health in this allergic setting. Thus, identifying ways to turn off specific signals instigated by fungal allergens in epithelial cells would offer valuable therapeutic benefit to the many individuals stricken with allergic asthma.
Several excellent reviews have been written on the topics of lung epithelial cell development and maintenance [9], pulmonary barrier immunity to bacterial and viral pathogens [10, 11••], and epithelium-dependent allergic responses to model allergens, such as ovalbumin and house dust mite extracts [12]. This review will discuss recent advances in our understanding of how epithelial cells recognize and respond to the threat of fungal invasion and promote antifungal immunity. We will also delve into how epithelial cells drive allergic asthma by mishandling the exposure to normally innocuous fungi and fungal products. To fully appreciate the inherent complexity of the epithelium and its interaction with a broad repertoire of immune cells, this review will focus mainly on in vivo studies published within the past several years.
Section snippets
Epithelial cells and invasive fungal infection
Only a handful of reports in the literature address the role of the epithelium in combating invasive fungal infection in vivo (Figure 3). The challenge of applying reductionist science in a highly complex system has likely stymied this field. However, the availability of conditional genetics to manipulate gene expression in cell subsets, in addition to intravital imaging of the interaction of lung epithelial cells and fungi, will facilitate in vivo studies of epithelial cells and antifungal
Epithelial cells promote allergic disease
Allergic (also known as ‘type-2’) responses did not evolve to cause disease. Rather, these responses are known to assist in beneficial wound healing, and aid in the expulsion of invertebrate parasites. Thus, current paradigms assign fungal-associated allergic responses to two general pathways. First, fungal proteases are unequivocally important products of fungi that are directly linked to allergic asthma in humans. It has been posited and empirically substantiated that proteases co-opt host
Concluding remarks
Several complex biological systems involving lung stroma and immune cells intersect shortly after fungi are inhaled into the lungs. The epithelial lining of the airways senses the presence of fungi and responds by summoning immune cells into action. Upon arrival, a network of diverse immune cells enacts their effective antimicrobial functions. If fungi attach to the epithelial cell surface, penetrate the lung parenchyma, and avoid immune surveillance, then invasive disease ensues. All three
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by NIH grants AI035681 and AI040996 (BSK) and by postdoctoral fellowship grants from the Hartwell Foundation and the NIH (T32 HL007899) to DLW. We thank Robert Gordon (Pediatrics) for assistance with graphic illustrations.
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