Aspergillus fumigatus: Principles of Pathogenesis and Host Defense

Abstract

Aspergillus fumigatus is a ubiquitous saprophytic mold (67) that forms airborne spores (conidia). Humans inhale, on average, hundreds of these infectious propagules daily. In immune competent hosts, these encounters are of no further significance—conidia are killed and cleared by cells of the pulmonary immune system. However, disease occurs when the host response is either too strong or too weak. Thus, understanding how the host interacts with the organism to define this balance is a critical goal, the successful pursuit of which requires recognition of the dynamic nature of both fungal and host molecular participants. In immunocompromised hosts, A. fumigatus represents a major cause of morbidity and mortality. This patient population is expanding due to the increasing use of transplantation for end organ disease, the development of immunosuppressive and myeloablative therapies for autoimmune and neoplastic disease, and the human immunodeficiency virus/AIDS pandemic (38). A. fumigatus is the most common invasive mold infection in these patients, and mortality rates exceed 50% in high-risk groups, such as leukemic patients and hematopoietic stem cell transplant recipients (74). Sensitivity to A. fumigatus antigens is associated with asthma, the prevalence of which is increasing in the developed world, though proving causation has been difficult (49, 54). Regardless, this increased prevalence brings a parallel rise in the number of individuals predisposed to allergic bronchopulmonary aspergillosis, a disease associated with aberrant responses to Aspergillus antigens in the setting of chronic inflammation. The spectrum of invasive, semi-invasive, and allergic disease caused by A. fumigatus is reviewed in several outstanding articles (9, 94). The study of A. fumigatus molecules involved in virulence has been hampered by the lack of an identifiable sexual cycle, limiting classical genetic analysis (21). A recent study, however, indicates that A. fumigatus encodes distinct mating-type loci and the pheromone machinery required for sexual mating (103). Nonetheless, within the past decade, researchers have developed and refined experimental tools to generate mutant strains by homologous recombination (21, 35, 62, 152, 154), utilized RNA interference to repress endogenous transcripts (95), and expressed heterologous genes in A. fumigatus under the control of drug-inducible regulatory elements (145). The completion of the A. fumigatus genome (98) has accelerated gene structure and function studies and made possible comparative genomic analyses with other sequenced Aspergillus species (Aspergillus oryzae and Aspergillus nidulans), as well as other genera of pathogenic (e.g., Candida albicans and Cryptococcus neoformans) and nonpathogenic (e.g., Saccharomyces cerevisiae) fungi. An important insight from the genomes has been that A. fumigatus does not share a common set of genes with other fungal pathogens (98). The types of hosts that are susceptible to invasive aspergillosis and the lack of unique pathways conserved among pathogenic fungi underscore the importance of the host contribution to pathogenesis. Damage from A. fumigatus can result from fungal growth and tissue invasion or from inflammatory cells recruited to sites of infection (130). Included in the latter are responses that are ineffective in clearing the organism, occur in the process of immune reconstitution, or are associated with allergy. For example, in a murine model of chronic granulomatous disease, in which mice have defective phagocyte oxidase systems, administration of killed hyphae results in chronic inflammation due to persistence of fungal elements (92). From the perspective of the mammalian immune system, A. fumigatus represents an organism with continuous respiratory tract exposure that must be cleared from terminal airways with an immune response calibrated to avoid fungal tissue invasion, as well as inflammation-induced tissue damage. Here, we review our growing understanding of the interface between A. fumigatus and host defense mechanisms, with an emphasis on invasive disease in humans and small animal models.