In silico modeling of spore inhalation reveals fungal persistence following low dose exposure

Abstract

The human lung is constantly exposed to spores of the environmental mould Aspergillus fumigatus, a major opportunistic pathogen. The spectrum of resultant disease is the outcome of complex host-pathogen interactions, an integrated, quantitative understanding of which lies beyond the ethical and technical reach permitted by animal studies. Here we construct a mathematical model of spore inhalation and clearance by concerted actions of macrophages and neutrophils, and use it to derive a mechanistic understanding of pathogen clearance by the healthy, immunocompetent host. In particular, we investigated the impact of inoculum size upon outcomes of single-dose fungal exposure by simulated titrations of inoculation dose, from 106 to 102 spores. Simulated low-dose (102) spore exposure, an everyday occurrence for humans, revealed a counter-intuitive prediction of fungal persistence (>3 days). The model predictions were reflected in the short-term dynamics of experimental murine exposure to fungal spores, thereby highlighting the potential of mathematical modelling for studying relevant behaviours in experimental models of fungal disease. Our model suggests that infectious outcomes can be highly dependent upon short-term dynamics of fungal exposure, which may govern occurrence of cyclic or persistent subclinical fungal colonisation of the lung following low dose spore inhalation in non-neutropenic hosts.

Real-time visualization of immune cell clearance of Aspergillus fumigatus spores and hyphae

“…For example, persistence of live A. fumigatus conidia for more than several days in both mouse (Tanaka et al, 2015) and zebrafish (Knox et al, 2014) models supports the efficacy of fungal spore defences (Aimanianda et al, 2009; Akoumianaki et al, 2016) conferring a tolerance to host inflicted stress. Furthermore, as a certain percentage of spores persist in vivo it is still unclear the spatial and temporal factors surrounding fungal killing.…”

Anti-Aspergillus Activities of the Respiratory Epithelium in Health and Disease

“…Several, currently insurmountable, technical challenges might be usefully circumvented by the use of computational approaches. For example, in support of a protective role for AEC-mediated activities, agent-based modelling of the human alveolus predicts that chemotactic signalling by AECs is required for the efficient recruitment of alveolar macrophages during early A. fumigatus infection [ 85 ] and low-dose exposure to A. fumigatus spores prompts fungal persistence in both in silico and murine models of pulmonary aspergillosis [ 85 ].…”

Host Response to Pulmonary Fungal Infections: a Highlight on Cell-Driven Immunity to Cryptococcus Species and Aspergillus fumigatus

“…In immunocompetent hosts, neutrophils form complexes with conidia that possess NADPH oxidase activity, thereby inhibiting germination [118]. Using in silico modeling, a recent report demonstrated that 6–17 hours after initial exposure, neutrophil- rather than macrophage-mediated killing of Aspergillus is the dominant conidiacidal response[119]. In addition, iron sequestration by lactoferrin secreted in neutrophilic granules is involved in restricting the initial germination of conidia [120, 121].…”