LA - ICVS/3B's - Associate Laboratory

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Genetic determinants of fungi-induced ROS production are associated with the risk of invasive pulmonary aspergillosis

Publication . Matzaraki, Vasiliki; Beno, Alexandra; Jaeger, Martin; Gresnigt, Mark S.; Keur, Nick; Boahen, Collins; Cunha, Cristina; Gonçalves, Samuel M.; Leite, Luis; Lacerda, João; Campos, António; van de Veerdonk, Frank L.; Joosten, Leo; Netea, Mihai G.; Carvalho, Agostinho; Kumar, Vinod

Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10-6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.

2022Journal article

Open access

Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis

Publication . Gonçalves, Samuel M.; Antunes, Daniela; Leite, Luis; Mercier, Toine; Horst, Rob Ter; Vieira, Joana; Espada, Eduardo; Pinho Vaz, Carlos; Branca, Rosa; Campilho, Fernando; Freitas, Fátima; Ligeiro, Dário; Marques, António; van de Veerdonk, Frank L.; Joosten, Leo A. B.; Lagrou, Katrien; Maertens, Johan; Netea, Mihai G.; Lacerda, João; Campos, António; Cunha, Cristina; Carvalho, Agostinho

Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at the interindividual level. In this study, we identify a key role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the immunometabolic responses to Aspergillus fumigatus. A genetic association study performed in 439 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and corresponding donors revealed that the donor, but not recipient, rs646564 variant in the PFKFB3 gene increased the risk of invasive pulmonary aspergillosis (IPA) after transplantation. The risk genotype impaired the expression of PFKFB3 by human macrophages in response to fungal infection, which was correlated with a defective activation of glycolysis and the ensuing antifungal effector functions. In patients with IPA, the risk genotype was associated with lower concentrations of cytokines in the bronchoalveolar lavage fluid samples. Collectively, these findings demonstrate the important contribution of genetic variation in PFKFB3 to the risk of IPA in patients undergoing HSCT and support its inclusion in prognostic tools to predict the risk of fungal infection in this clinical setting. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. In this study, we report the contribution of genetic variation in the key glycolytic activator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) to the risk of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation. The PFKFB3 genotype associated with increased risk of infection was correlated with an impairment of the antifungal effector functions of macrophages in vitro and in patients with IPA. This work highlights the clinical relevance of genetic variation in PFKFB3 to the risk of IPA and supports its integration in risk stratification and preemptive measures for patients at high risk of IPA.

2021-05-28Journal 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

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

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