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

Reiko J Tanaka,Katarina Vrcelj,Elaine Bignell,Carmelina Vinci,Darius Armstrong-James,Neville J Boon,Anita Nguyen

doi:10.1038/srep13958

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.

Highlights

IntroductionThe relative potency of these cell subsets in effecting fungal clearance, and the mechanistic basis of their co-operative activity, remains unknown
Inhalation of A. fumigatus spores leads to varying pathologic outcomes depending on the host immune status[17]
We developed an ordinary differential equation model, comprising of eight biological processes (Fig. 1), which predicts and quantifies the short-term concerted actions of macrophages and neutrophils in response to fungal challenge and which determines the outcomes of fungal spore inhalation

Summary

Introduction

The relative potency of these cell subsets in effecting fungal clearance, and the mechanistic basis of their co-operative activity, remains unknown Such information cannot be derived from in vitro experimentation, and cannot be readily quantified in whole animal models of disease. Compared with human infections, which are likely initiated from several tens (or fewer) of spores[8], mice challenged with high numbers of spores have a much shorter duration of disease and a heightened severity of infection Such excessive fungal challenge might overwhelm residual host defences, prompting physiologically irrelevant host responses. Disparate short-term dynamics, in response to low- and high dose fungal exposure, emerged as a critical, counter-intuitive finding of the study which was experimentally validated thereby prompting new theories on the mechanistic basis of subclinical A. fumigatus persistence in the human lung. This work highlights the potential of mathematical modeling approaches for studying clinically relevant behaviors in experimental models of fungal disease

Methods

Results

Conclusion