New developments in Aspergillus fumigatus and host reactive oxygen species responses

Abstract

Aspergillus fumigatus is a filamentous fungus abundant in the environment and the most common causative agent of a spectrum of human diseases collectively termed aspergillosis. Invasive pulmonary aspergillosis is caused by deficiencies in innate immune function that result in the inability of the host to clear inhaled Aspergillus conidia that then germinate and form invasive hyphae. Myeloid cells, and their ability to generate reactive oxygen species (ROS), are essential for conidia clearance from the host. To combat ROS, A. fumigatus employs an expansive antioxidant system, though how these canonical antioxidant mechanisms contribute to infection initiation and disease progression remain to be fully defined. Recent research has identified noncanonical pathways in the A. fumigatus ROS response and new host populations with ROS deficiencies that are at-risk for invasive aspergillosis. Here, we highlight recent developments in the understanding of ROS at the interface of the dynamic A. fumigatus-host interaction.

Figure 1.. A model of host and fungal ROS-dependent responses upon A. fumigatus immune recognition by a myeloid cell.

A. fumigatus conidia (green circle) is illustrated inside of the phagolysosome (blue circle) of a myeloid cell. The fungus can encounter various sources of ROS (labeled in black bold) during immune recognition. These sources include exogenous ROS generated by host NADPH oxidase and mitochondria in addition to endogenous ROS generated by the electron transport chain (ETC) in fungal mitochondrion or NADPH oxidase (NOX) during growth. Effective clearance of A. fumigatus from the mammalian lung is contingent on the function of host NADPH oxidase. Host genetic variation and therapeutics (labeled in red bold text) impact the ability of NADPH oxidase to efficiently generate superoxide anion. TNFα supplementation has been demonstrated to rescue defects in neutrophil function caused by Bruton’s tyrosine kinase (BTK) inhibitors. Host mitochondrial ROS generated via reverse electron transport (RET) is important for macrophage function and production of TNFα and IL-β which are then secreted into the extracellular environment. The response of A. fumigatus to ROS includes a complex transcriptional response which regulates canonical antioxidants such as superoxide dismutases, catalases, and thiol proteins. General stress response factors SakA, Emi1, and SpfA promote fungal survival during oxidative stress. Overexpression of the survivin homolog Bir1 or loss of cytochrome c (CycA) promote fungal survival upon ROS or leukocyte challenge. Solid lines represent interactions supported with murine pulmonary infection data. Dashed lines indicate interactions supported with in vitro data, but not fully tested in a murine pulmonary infection model. Proteins highlighted in magenta indicate A. fumigatus factors that influence infection in immunocompromised models of IPA. Figure generated with Biorender