Host directed medicine in invasive fungal infection

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Publications

Serum amyloid P component is an essential element of resistance against Aspergillus fumigatus

Publication . Doni, Andrea; Parente, Raffaella; Laface, Ilaria; Magrini, Elena; Cunha, Cristina; Colombo, Federico Simone; Lacerda, João; Campos, António; Mapelli, Sarah N.; Petroni, Francesca; Porte, Rémi; Schorn, Tilo; Inforzato, Antonio; Mercier, Toine; Lagrou, Katrien; Maertens, Johan; Lambris, John D.; Bottazzi, Barbara; Garlanda, Cecilia; Botto, Marina; Carvalho, Agostinho; Mantovani, Alberto

Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs-/- mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs-/- mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.

2021Journal article

Open access

Aspergillus fumigatus hijacks human p11 to redirect fungal-containing phagosomes to non-degradative pathway

Publication . Jia, Lei-Jie; Rafiq, Muhammad; Radosa, Lukáš; Hortschansky, Peter; Cunha, Cristina; Cseresnyés, Zoltán; Krüger, Thomas; Schmidt, Franziska; Heinekamp, Thorsten; Straßburger, Maria; Löffler, Bettina; Doenst, Torsten; Lacerda, João; Campos, António; Figge, Marc Thilo; Carvalho, Agostinho; Kniemeyer, Olaf; Brakhage, Axel A.

The decision whether endosomes enter the degradative or recycling pathway in mammalian cells is of fundamental importance for pathogen killing, and its malfunctioning has pathological consequences. We discovered that human p11 is a critical factor for this decision. The HscA protein present on the conidial surface of the human-pathogenic fungus Aspergillus fumigatus anchors p11 on conidia-containing phagosomes (PSs), excludes the PS maturation mediator Rab7, and triggers binding of exocytosis mediators Rab11 and Sec15. This reprogramming redirects PSs to the non-degradative pathway, allowing A. fumigatus to escape cells by outgrowth and expulsion as well as transfer of conidia between cells. The clinical relevance is supported by the identification of a single nucleotide polymorphism in the non-coding region of the S100A10 (p11) gene that affects mRNA and protein expression in response to A. fumigatus and is associated with protection against invasive pulmonary aspergillosis. These findings reveal the role of p11 in mediating fungal PS evasion.

2023Journal article

Open access

MAVS expression in alveolar macrophages is essential for host resistance against Aspergillus fumigatus

Publication . Wang, Xi; Cunha, Cristina; Grau, Madeleine S.; Robertson, Shelly J.; Lacerda, João; Campos, António; Lagrou, Katrien; Maertens, Johan; Best, Sonja M.; Carvalho, Agostinho; Obar, Joshua J.

Our recent data demonstrate a critical role of the RIG-I-like receptor family in regulating antifungal immunity against Aspergillus fumigatus in a murine model. However, the importance of this pathway in humans and the cell types that use this innate immune receptor family to detect A. fumigatus remain unresolved. In this study, using patients who underwent hematopoietic stem cell transplantation, we demonstrate that a polymorphism in human MAVS present in the donor genome was associated with the incidence of invasive pulmonary aspergillosis. Moreover, in a separate cohort of confirmed invasive pulmonary aspergillosis patients, polymorphisms in the IFIH1 gene alter the inflammatory response, including IFN-responsive chemokines. Returning to our murine model, we now demonstrate that CD11c+ Siglec F+ alveolar macrophages require Mavs expression to maintain host resistance against A. fumigatus. Our data support the role of MAVS signaling in mediating antifungal immunity in both mice and humans at least in part through the role of MAVS-dependent signaling in alveolar macrophages.

2022Journal article

Restricted access