Recent Advances in Fungal Infections: From Lung Ecology to Therapeutic Strategies With a Focus on Aspergillus spp

Abstract

Fungal infections are estimated to be the main cause of death for more than 1.5 million people worldwide annually. However, fungal pathogenicity has been largely neglected. This is notably the case for pulmonary fungal infections, which are difficult to diagnose and to treat. We are currently facing a global emergence of antifungal resistance, which decreases the chances of survival for affected patients. New therapeutic approaches are therefore needed to face these life-threatening fungal infections. In this review, we will provide a general overview on respiratory fungal infections, with a focus on fungi of the genus Aspergillus. Next, the immunological and microbiological mechanisms of fungal pathogenesis will be discussed. The role of the respiratory mycobiota and its interactions with the bacterial microbiota on lung fungal infections will be presented from an ecological perspective. Finally, we will focus on existing and future innovative approaches for the treatment of respiratory fungal infections.

Keywords: aspergillosis; chronic respiratory disease; disease management; environmental interference; live biotherapeutic products; microbiome; mycobiome.

FIGURE 1

Clearance of Aspergillus conidia in the immunocompetent host. (A) Aspergillus spp. conidia are transmitted through air and every individual inhales thousands of conidia every day. (B) In the immunocompetent host, most of the inhaled conidia are trapped by the mucus layer secreted by the tracheal and bronchial epithelium, and are efficiently eliminated through mucociliary clearance. (C) Due to their small size, conidia can eventually reach the alveoli, where they are phagocytosed by alveolar macrophages. Modified from Palmieri (170).

FIGURE 2

Disease spectrum of pulmonary aspergillosis. This diagram summarizes the diverse pathologies caused by Aspergillus spp., due to improper elimination of conidia by mucociliary clearance or macrophage phagocytosis following inhalation. Depending on the immune status of the host, pulmonary aspergillosis can range from allergic reaction (hypersensitivity) to life-threatening invasive infection (severe immunosuppression). Moreover, current burden and treatment information are indicated. ABPA, allergic bronchopulmonary aspergillosis; CPA, chronic pulmonary aspergillosis; IA, invasive aspergillosis. Modified from Palmieri (170).

FIGURE 3

Roles of acidification and alkalinization mechanisms in fungal pathogenesis. This scheme summarizes the different roles of acidification and alkalinization mechanisms in fungal pathogenesis for the colonization of the host tissues.

FIGURE 4

Disease pyramid. The onset of a disease depends on the interplay between the host, the pathogen, the environment, and the host microbiome. Host susceptibility mainly depends on genetic factors and immune status. The main factor for the successful colonization of the host tissues by the pathogen is its virulence. The environment corner refers to the host lung microenvironmental parameters and include among others pH, calcium (Ca²⁺) and iron (Fe²⁺) concentrations. Host microbiota community structure can also influence the establishment of the pathogen. Icons have been created using Biorender.com. Modified from Palmieri (170).