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

Alayna K Caffrey-Carr^1,2, Kimberly M Hilmer¹, Caitlin H Kowalski²

¹Department of Microbiology and Immunology, Montana State University, Bozeman, MT, United States.

Frontiers in Immunology

|January 30, 2018

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.

Insights

The study reveals that 5-Lipoxygenase (5-LO) and Leukotriene B4 (LTB4) are crucial for controlling pulmonary Aspergillus fumigatus infections by aiding leukocyte recruitment. This innate immune pathway is vital for host defense against fungal lung infections.

Area of Science:

Immunology
Mycology
Biochemistry

Background:

Innate immunity is essential for controlling fungal infections like aspergillosis.
Neutrophil recruitment and activation are critical for host defense against Aspergillus fumigatus.
The specific inflammatory pathways involved in anti-fungal immunity require further definition.

Purpose of the Study:

To investigate the role of 5-Lipoxygenase (5-LO) and Leukotriene B4 (LTB4) in host defense against pulmonary Aspergillus fumigatus.
To determine the cellular requirements for 5-LO activity in anti-fungal responses.
To explore the regulation of LTB4 production during fungal infection.

Main Methods:

Utilized a murine model of pulmonary Aspergillus fumigatus infection.
Assessed the impact of 5-LO deficiency on fungal burden and host survival.
Investigated leukocyte recruitment and activation in the lungs.
Examined the role of radiosensitive cells and hypoxia-inducible factor-1α in LTB4 production.

Main Results:

5-Lipoxygenase (5-LO) and Leukotriene B4 (LTB4) are critical for effective host defense against pulmonary Aspergillus fumigatus.
The anti-fungal response mediated by 5-LO is dependent on radiosensitive cells.
In vivo LTB4 production is partially regulated by myeloid-derived hypoxia-inducible factor-1α.
The protective role of LTB4 is fungal-strain-dependent.

Conclusions:

Host-derived leukotriene synthesis, specifically involving 5-LO and LTB4, plays a significant role in innate immunity against Aspergillus fumigatus.
Targeting the 5-LO/LTB4 pathway may offer therapeutic strategies for invasive pulmonary aspergillosis.
Understanding the fungal-strain-dependent nature of this response is crucial for developing effective treatments.

Read full analysis

Keywords:

Aspergillus fumigatus eosinophils fungal infection hypoxia inducible factor-1α leukotriene B4 leukotrienes neutrophils respiratory tract infections

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