Persistence versus Escape: Aspergillus terreus and Aspergillus fumigatus Employ Different Strategies during Interactions with Macrophages

Abstract

Invasive bronchopulmonary aspergillosis (IBPA) is a life-threatening disease in immunocompromised patients. Although Aspergillus terreus is frequently found in the environment, A. fumigatus is by far the main cause of IBPA. However, once A. terreus establishes infection in the host, disease is as fatal as A. fumigatus infections. Thus, we hypothesized that the initial steps of disease establishment might be fundamentally different between these two species. Since alveolar macrophages represent one of the first phagocytes facing inhaled conidia, we compared the interaction of A. terreus and A. fumigatus conidia with alveolar macrophages. A. terreus conidia were phagocytosed more rapidly than A. fumigatus conidia, possibly due to higher exposure of β-1,3-glucan and galactomannan on the surface. In agreement, blocking of dectin-1 and mannose receptors significantly reduced phagocytosis of A. terreus, but had only a moderate effect on phagocytosis of A. fumigatus. Once phagocytosed, and in contrast to A. fumigatus, A. terreus did not inhibit acidification of phagolysosomes, but remained viable without signs of germination both in vitro and in immunocompetent mice. The inability of A. terreus to germinate and pierce macrophages resulted in significantly lower cytotoxicity compared to A. fumigatus. Blocking phagolysosome acidification by the v-ATPase inhibitor bafilomycin increased A. terreus germination rates and cytotoxicity. Recombinant expression of the A. nidulans wA naphthopyrone synthase, a homologue of A. fumigatus PksP, inhibited phagolysosome acidification and resulted in increased germination, macrophage damage and virulence in corticosteroid-treated mice. In summary, we show that A. terreus and A. fumigatus have evolved significantly different strategies to survive the attack of host immune cells. While A. fumigatus prevents phagocytosis and phagolysosome acidification and escapes from macrophages by germination, A. terreus is rapidly phagocytosed, but conidia show long-term persistence in macrophages even in immunocompetent hosts.

Distinct Innate Immune Phagocyte Responses to Aspergillus fumigatus Conidia and Hyphae in Zebrafish Larvae

“…1B). Previous studies have shown that innate phagocytes can kill A. fumigatus conidia over time in vitro (34). Therefore, to determine if conidial killing accompanied immunocompetent larval survival in vivo, pools of 20 larvae were homogenized at 0, 1, 3, 5, and 7 days postinfection (dpi) to assess the average fungal burden throughout the course of infection.…”

Surface Structure Characterization of Aspergillus fumigatus Conidia Mutated in the Melanin Synthesis Pathway and Their Human Cellular Immune Response

“…The role of the conidial melanin in the A. fumigatus virulence has been studied by using either melanin ghosts or the pigmentless mutant, wherein the PKSP gene, which encodes a protein involved in the first step of melanin biosynthesis, has been deleted (4,9,(16)(17)(18)(19), These reports demonstrated that melanin protects the conidia against reactive oxygen species, masks the recognition of various A. fumigatus pattern-associated molecular patterns, inhibits macrophage apoptosis and phagolysosome fusion, and attenuates the host immune response. All of these functions of melanin contribute to the increased survival of conidia in macrophages and promote the dissemination of A. fumigatus within the host.…”

Identification and characteristics of biological agents in work environment of medical emergency services in selected ambulances

“…This species is the main etiologic agent of pulmonary and systemic aspergillosis in immunocompromised persons. It may occur as an opportunistic pathogen or as an allergen, moreover, it is found on the list of harmful biological agents found in the workplace [23,[34][35][36]. However, only exposure to high levels of airborne filamentous fungi (e.g., 10 10 spores/m 3 ) associated with bioaerosols may result in sickness partly caused by mycotoxins [37].…”