Abstract
In immunocompromised individuals, Aspergillus fumigatus causes invasive fungal disease that is often difficult to treat. Exactly how immune mechanisms control A. fumigatus in immunocompetent individuals remains unclear. Here, we use transparent zebrafish larvae to visualize and quantify neutrophil and macrophage behaviors in response to different A. fumigatus strains. We find that macrophages form dense clusters around spores, establishing a protective niche for fungal survival. Macrophages exert these protective effects by inhibiting fungal germination, thereby inhibiting subsequent neutrophil recruitment and neutrophil-mediated killing. Germination directly drives fungal clearance as faster-growing CEA10-derived strains are killed better in vivo than slower-growing Af293-derived strains. Additionally, a CEA10 pyrG-deficient strain with impaired germination is cleared less effectively by neutrophils. Host inflammatory activation through Myd88 is required for killing of a CEA10-derived strain but not sufficient for killing of an Af293-derived strain, further demonstrating the role of fungal-intrinsic differences in the ability of a host to clear an infection. Altogether, we describe a new role for macrophages in the persistence of A. fumigatus and highlight the ability of different A. fumigatus strains to adopt diverse modes of virulence.
Highlights
Immunocompromised patients are susceptible to invasive fungal infections, including aspergillosis
Humans inhale hundreds of Aspergillus fumigatus spores from the environment every day and yet almost all immunocompetent individuals successfully contend with the fungal infection
By following individual larvae with both labeled macrophage nuclei and neutrophils throughout a 5 day infection, we aimed to determine both differences in immune cell recruitment within larvae over time and population-level differences between larvae infected with a CEA17 KU80Δ (CEA10)-derived strain versus an Af293-derived strain
Summary
Humans inhale hundreds of Aspergillus fumigatus spores from the environment every day and yet almost all immunocompetent individuals successfully contend with the fungal infection. The development of successful immunotherapy-based treatments to this infection requires a more comprehensive understanding of the interplay of immune mechanisms that control Aspergillus in vivo. The innate immune system is generally sufficient for A. fumigatus clearance, with both macrophages and neutrophils playing major roles [3]. Neutrophils, on the other hand, are consistently required in mice in response to Aspergillus [6, 8], and neutropenia is a key risk factor for patients in the development of invasive aspergillosis [9]. The full extent of macrophage/monocyte and neutrophil interactions throughout the course of infection, and their effect on fungal growth and clearance, are not known
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