Albumin orchestrates a natural host defence mechanism against mucormycosis
Antonis Pikoulas, Ioannis Morianos, Vassilis Nidris Nidris, Rania Hamdy, Evangelia Intze, Ángeles López-López, María Morán-Garrido, Valliappan Muthu, Maria Halabalaki, Varvara Papaioanou, Maria Papadovasilaki, Irene Kyrmizi, Yiyou Gu, Sandra Camunas-Alberca, Robina Aerts, Toine Mercier, Yuri Vanbiervliet, Cho Sung-Yeon, Amy Spallone, Ying Jiang, Dimitrios Samonakis, Efstathios Kastritis, Carlos Lax, Maria Tzardi, Aristides G. Eliopoulos, Konstantina Georgila, Agostinho Carvalho, Oliver Kurzai, Shivaprakash Mandya Rudramurthy, Caroline Elie, Fanny Lanternier, Kyriakos Petratos, Victoriano Garre, Ηλίας Δράκος, Johan Maertens, Vincent M. Bruno, Dimitrios P. Kontoyiannis, Coral Barbas, Sameh S. M. Soliman, Ashraf S. Ibrahim, Georgios Chamilos
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. Albumin selectively inhibits Mucorales growth through the release of bound free fatty acids.