Host-Derived Leukotriene B4 Is Critical for Resistance against Invasive Pulmonary Aspergillosis.

Alayna K. Caffrey-Carr,Kimberly M. Hilmer,Joshua J. Obar,Caitlin H. Kowalski,Rachel M. Temple,Robert A. Cramer,Kelly M. Shepardson

doi:10.3389/fimmu.2017.01984

Alayna K. Caffrey-Carr, Kimberly M. Hilmer + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2017.01984

Copy DOI

Abstract

Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how immune competent hosts maintain control of fungal infections while constantly being exposed to fungi is rapidly emerging. It is known that timely neutrophil recruitment to and activation in the lungs is critical to the host defense against development of invasive pulmonary aspergillosis, but the inflammatory sequelae necessary remains to be fully defined. Here, we show that 5-Lipoxygenase (5-LO) and Leukotriene B4 (LTB4) are critical for leukocyte recruitment and resistance to pulmonary A. fumigatus challenge in a fungal-strain-dependent manner. 5-LO activity was needed in radiosensitive cells for an optimal anti-fungal response and in vivo LTB4 production was at least partially dependent on myeloid-derived hypoxia inducible factor-1α. Overall, this study reveals a role for host-derived leukotriene synthesis in innate immunity to A. fumigatus.

Highlights

Aspergillus fumigatus is a ubiquitous mold that causes severe infections, such as invasive pulmonary aspergillosis (IPA), in the immunocompromised population
We found that Leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLT) showed increased production after A. fumigatus CEA10 challenge
Because the early recruitment of neutrophils is needed for host resistance to invasive A. fumigatus infection [6], we addressed whether fungal growth was enhanced in the Ltb4r1−/− animals

Summary

Introduction

Aspergillus fumigatus is a ubiquitous mold that causes severe infections, such as invasive pulmonary aspergillosis (IPA), in the immunocompromised population. Due to a combination of (i) difficulty in diagnosis, (ii) limited efficacy of anti-fungal drugs coupled with the emergence of drug resistance, and (iii) a lack of an effective vaccine against Aspergillus spp., mortality rates of IPA are extremely high [1, 2] To this end, development of novel immunomodulatory strategies that can potentially be combined with current anti-fungal treatments is an active area of research. In individuals that lack this immune response, conidia are able to germinate and grow within the lung causing tissue damage and disease. These initial encounters are important in the recruitment and activation of neutrophils, inflammatory monocytes, NK cells, and CD4 T cells to further control fungal growth within the lung [5]. Neutrophils have long been recognized as one of the key effector cells necessary for resistance against Aspergillus infection and neutropenia is a key risk factor for patients that will develop IPA [6]

Methods

Results

Conclusion