Albumin orchestrates a natural host defence mechanism against mucormycosis
Antonis Pikoulas1, Ioannis Morianos1,2, Vassilis Nidris1,2
1School of Medicine, University of Crete, Voutes, Heraklion, Greece.
Abstract:
Mucormycosis is an emerging, life-threatening human infection caused by Mucorales fungi1-3. Metabolic disorders uniquely predispose an ever-expanding group of patients to mucormycosis through poorly understood mechanisms1,2,4,5, suggesting that uncharacterized host metabolic effectors may confer protective immunity against this infection. Here we uncover a master regulatory role of albumin in host defence against Mucorales through the modulation of fungal pathogenicity. Our initial studies identified severe hypoalb uminaemia as a prominent metabolic abnormality and an independent biomarker of poor mucormycosis outcome across three distinct cohorts of patients with mucormycosis. Notably, purified albumin selectively inhibits Mucorales growth among a range of pathogens, and albumin-deficient mice display susceptibility specifically to mucormycosis. The antifungal activity of albumin is mediated by the release of bound free fatty acids (FFAs). Albumin prevents FFA oxidation, which otherwise abolishes their antifungal properties, and sera from patients with mucormycosis display high levels of oxidized FFAs. Physiologically, albumin-bound FFAs suppress the expression of key virulence factors by inhibiting protein synthesis, the reby rendering Mucorales avirulent in vivo. Overall, we identify a host defence mechanism that directs the pathogen to suppress its pathogenicity program in response to unfavourable metabolic cues regulated by albumin. These findings have major implications for the pathogenesis and management of mucormycosis.
Insights
Low albumin levels (hypoalbuminemia) are linked to poor outcomes in mucormycosis, a fungal infection. Albumin protects against Mucorales fungi by releasing fatty acids that inhibit fungal growth and virulence.
Area of Science:
- Mycology
- Immunology
- Metabolic Medicine
Background:
- Mucormycosis is a severe fungal infection caused by Mucorales.
- Metabolic disorders are known risk factors, but mechanisms of host defense are unclear.
- Identifying host metabolic factors is crucial for understanding and treating mucormycosis.
Purpose of the Study:
- To investigate the role of albumin in host defense against Mucorales.
- To determine if hypoalbuminemia is a biomarker for mucormycosis outcomes.
- To elucidate the mechanism by which albumin confers protection.
Main Methods:
- Analysis of patient cohorts with mucormycosis to correlate albumin levels with outcomes.
- In vitro testing of purified albumin's effect on Mucorales growth.
- Studies in albumin-deficient mice to assess susceptibility to mucormycosis.
- Investigation of the role of free fatty acids (FFAs) in albumin's antifungal activity.
Main Results:
- Severe hypoalbuminemia was identified as a biomarker for poor mucormycosis prognosis.
- Albumin selectively inhibited Mucorales growth and protected albumin-deficient mice.
- Albumin's antifungal activity is mediated by bound free fatty acids (FFAs), which are protected from oxidation.
- Albumin-bound FFAs suppress fungal virulence factors by inhibiting protein synthesis.
Conclusions:
- Albumin plays a critical role in host defense against Mucorales by modulating fungal pathogenicity.
- Hypoalbuminemia is a significant risk factor and biomarker for mucormycosis.
- Albumin-bound FFAs represent a key effector mechanism in combating mucormycosis.
- Findings offer new insights into mucormycosis pathogenesis and potential therapeutic strategies.
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