Infection-Mediated Priming of Phagocytes Protects against Lethal Secondary Aspergillus fumigatus Challenge.

Amélie Savers,Jean-Marc Cavaillon,Gregory Jouvion,Orhan Rasid,Oumaïma Ibrahim-Granet,Bernhard Ryffel,Gerard Eberl,Matthias Brock,Marianna Parlato

doi:10.1371/journal.pone.0153829

Abstract

Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection.

Highlights

Over the past decades, A. fumigatus has emerged as an important opportunistic fungus that can cause severe human lung damage [1]
To study the effect of “priming” on murine survival following a secondary challenge with conidia, we first infected immunecompetent BALB/c mice with a sublethal dose (“SL”) of 5×107 conidia of a bioluminescent A. fumigatus strain (S1 Fig)
When we investigated lung histology on day 2 after challenge, we observed that neutrophils and macrophages formed inflammatory foci that were mostly centered on bronchioles, extended to alveoli, and contained very rare A. fumigatus hyphae (Fig 1F)

Summary

Introduction

A. fumigatus has emerged as an important opportunistic fungus that can cause severe human lung damage [1]. While healthy individuals rapidly clear inhaled conidia, immunecompromised patients have impaired clearance mechanisms that permit conidial germination in lung tissues, resulting in life-threatening invasive pulmonary aspergillosis. Neutrophils, monocytes, and macrophages represent the first line of defense against fungal pathogens [2]. While alveolar macrophages have been shown to initiate the early inflammatory response [3], neutrophils are essential for fungal inactivation and, protection against invasive aspergillosis [4] [5] [6]. Phagocyte expression of surface recognition receptors is essential for anti-fungal responses. The C-type lectin receptor Dectin-1 recognizes β-1,3-glucan and can initiate and mediate phagocytosis and pro-inflammatory cytokine responses [7].

Methods

Results

Conclusion