THE ROLE OF INFLAMMASOME ACTIVATION IN HOST IMMUNITY TO FUNGAL INFECTION - The inflammasome-microbiota interplay in antifungal immunity

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Paving the way for predictive diagnostics and personalized treatment of invasive aspergillosis

Publication . Oliveira-Coelho, Ana; Rodrigues, Fernando; Campos, António; Lacerda, João; Carvalho, Agostinho; Cunha, Cristina

Invasive aspergillosis (IA) is a life-threatening fungal disease commonly diagnosed among individuals with immunological deficits, namely hematological patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation. Vaccines are not available, and despite the improved diagnosis and antifungal therapy, the treatment of IA is associated with a poor outcome. Importantly, the risk of infection and its clinical outcome vary significantly even among patients with similar predisposing clinical factors and microbiological exposure. Recent insights into antifungal immunity have further highlighted the complexity of host-fungus interactions and the multiple pathogen-sensing systems activated to control infection. How to decode this information into clinical practice remains however, a challenging issue in medical mycology. Here, we address recent advances in our understanding of the host-fungus interaction and discuss the application of this knowledge in potential strategies with the aim of moving toward personalized diagnostics and treatment (theranostics) in immunocompromised patients. Ultimately, the integration of individual traits into a clinically applicable process to predict the risk and progression of disease, and the efficacy of antifungal prophylaxis and therapy, holds the promise of a pioneering innovation benefiting patients at risk of IA.

2015Journal article

Open access

Genetic deficiency of NOD2 confers resistance to invasive aspergillosis

Publication . Gresnigt, Mark S.; Cunha, Cristina; Jaeger, Martin; Gonçalves, Samuel M.; Malireddi, R. K. Subbarao; Ammerdorffer, Anne; Lubbers, Rosalie; Oosting, Marije; Rasid, Orhan; Jouvion, Grégory; Fitting, Catherine; Jong, Dirk J. de; Lacerda, João; Campos, António; Melchers, Willem J. G.; Lagrou, Katrien; Maertens, Johan; Kanneganti, Thirumala-Devi; Carvalho, Agostinho; Ibrahim-Granet, Oumaima; van de Veerdonk, Frank L.

Invasive aspergillosis (IA) is a severe infection that can occur in severely immunocompromised patients. Efficient immune recognition of Aspergillus is crucial to protect against infection, and previous studies suggested a role for NOD2 in this process. However, thorough investigation of the impact of NOD2 on susceptibility to aspergillosis is lacking. Common genetic variations in NOD2 has been associated with Crohn's disease and here we investigated the influence of these genetic variations on the anti-Aspergillus host response. A NOD2 polymorphism reduced the risk of IA after hematopoietic stem-cell transplantation. Mechanistically, absence of NOD2 in monocytes and macrophages increases phagocytosis leading to enhanced fungal killing, conversely, NOD2 activation reduces the antifungal potential of these cells. Crucially, Nod2 deficiency results in resistance to Aspergillus infection in an in vivo model of pulmonary aspergillosis. Collectively, our data demonstrate that genetic deficiency of NOD2 plays a protective role during Aspergillus infection.

2018Journal article

Open access

PTX3 polymorphisms influence cytomegalovirus reactivation after stem-cell transplantation

Publication . Campos, Cláudia F.; Leite, Luís; Pereira, Paulo; Vaz, Carlos Pinho; Branca, Rosa; Campilho, Fernando; Freitas, Fátima; Ligeiro, Dário; Marques, António; Torrado, Egídio; Silvestre, Ricardo; Lacerda, João; Campos Jr., António; Cunha, Cristina; Carvalho, Agostinho

Background: Reactivation of latent human cytomegalovirus (CMV) in patients undergoing allogeneic stem-cell transplantation (HSCT) predisposes to several clinical complications and is therefore a major cause of morbidity and mortality. Although pentraxin-3 (PTX3) has been previously described to bind both human and murine CMV and mediate several host antiviral mechanisms, whether genetic variation in the PTX3 locus influences the risk of CMV infection is currently unknown. Methods: To dissect the contribution of genetic variation within PTX3 to the development of CMV infection, we analyzed described loss-of-function variants at the PTX3 locus in 394 recipients of HSCT and their corresponding donors and assessed the associated risk of CMV reactivation. Results: We report that the donor, but not recipient, h2/h2 haplotype in PTX3 increased the risk of CMV reactivation after 24 months following transplantation, with a significant effect on survival. Among recipients with h2/h2 donors, CMV seropositive patients as well as those receiving grafts from unrelated donors, regardless of the CMV serostatus, were more prone to develop viral reactivation after transplantation. Most importantly, the h2/h2 haplotype was demonstrated to display an influence toward risk of CMV reactivation comparable to that conferred by the unrelated status of the donor alone. Conclusions: Our findings demonstrate the important contribution of genetic variation in donor PTX3 to the risk of CMV reactivation in patients undergoing HSCT, highlighting a promising prognostic value of donor PTX3 to predict risk of CMV reactivation in this clinical setting.

2019Journal article

Open access

Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus

Publication . Stappers, Mark H. T.; Clark, Alexandra E.; Aimanianda, Vishukumar; Bidula, Stefan; Reid, Delyth M.; Asamaphan, Patawee; Hardison, Sarah E.; Dambuza, Ivy M.; Valsecchi, Isabel; Kerscher, Bernhard; Plato, Anthony; Wallace, Carol A.; Yuecel, Raif; Hebecker, Betty; da Glória Teixeira Sousa, Maria; Cunha, Cristina; Liu, Yan; Feizi, Ten; Brakhage, Axel A.; Kwon-Chung, Kyung J.; Gow, Neil A. R.; Zanda, Matteo; Piras, Monica; Zanato, Chiara; Jaeger, Martin; Netea, Mihai G.; van de Veerdonk, Frank L.; Lacerda, João; Campos, António; Carvalho, Agostinho; Willment, Janet A.; Latgé, Jean-Paul; Brown, Gordon D.

Resistance to infection is critically dependent on the ability of pattern recognition receptors to recognize microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which are central to antifungal immunity. These receptors activate key effector mechanisms upon recognition of conserved fungal cell-wall carbohydrates. However, several other immunologically active fungal ligands have been described; these include melanin, for which the mechanism of recognition is hitherto undefined. Here we identify a C-type lectin receptor, melanin-sensing C-type lectin receptor (MelLec), that has an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognizes melanin in conidial spores of Aspergillus fumigatus as well as in other DHN-melanized fungi. MelLec is ubiquitously expressed by CD31+ endothelial cells in mice, and is also expressed by a sub-population of these cells that co-express epithelial cell adhesion molecule and are detected only in the lung and the liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus. In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased the susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. MelLec therefore recognizes an immunologically active component commonly found on fungi and has an essential role in protective antifungal immunity in both mice and humans.

2018Journal article

Restricted access

Calcium sequestration by fungal melanin inhibits calcium–calmodulin signalling to prevent LC3-associated phagocytosis

Publication . Kyrmizi, Irene; Ferreira, Helena; Carvalho, Agostinho; Figueroa, Julio Alberto Landero; Zarmpas, Pavlos; Cunha, Cristina; Akoumianaki, Tonia; Stylianou, Kostas; Deepe, George S.; Samonis, George; Lacerda, João; Campos, António; Kontoyiannis, Dimitrios P.; Mihalopoulos, Nikolaos; Kwon-Chung, Kyung J.; El-Benna, Jamel; Valsecchi, Isabel; Beauvais, Anne; Brakhage, Axel A.; Neves, Nuno M.; Latge, Jean-Paul; Chamilos, Georgios

LC3-associated phagocytosis (LAP) is a non-canonical autophagy pathway regulated by Rubicon, with an emerging role in immune homeostasis and antifungal host defence. Aspergillus cell wall melanin protects conidia (spores) from killing by phagocytes and promotes pathogenicity through blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of LAP. However, the signalling regulating LAP upstream of Rubicon and the mechanism of melanin-induced inhibition of this pathway remain incompletely understood. Herein, we identify a Ca2+ signalling pathway that depends on intracellular Ca2+ sources from endoplasmic reticulum, endoplasmic reticulum-phagosome communication, Ca2+ release from phagosome lumen and calmodulin (CaM) recruitment, as a master regulator of Rubicon, the phagocyte NADPH oxidase NOX2 and other molecular components of LAP. Furthermore, we provide genetic evidence for the physiological importance of Ca2+-CaM signalling in aspergillosis. Finally, we demonstrate that Ca2+ sequestration by Aspergillus melanin inside the phagosome abrogates activation of Ca2+-CaM signalling to inhibit LAP. These findings reveal the important role of Ca2+-CaM signalling in antifungal immunity and identify an immunological function of Ca2+ binding by melanin pigments with broad physiological implications beyond fungal disease pathogenesis.

2018Journal article

Restricted access