Genetic deficiency of NOD2 confers resistance to invasive aspergillosis

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.We thank C. Wertz and M. Fanton D'Andon for providing Nod2-deficient mice, M. Schlotter for organizing patient inclusion, B. Rosler for assistance with flowcytometry. We also thank the NOD2-deficient patients for contributing to our study by providing blood samples. M.S.G. was supported by the Erasmus lifelong learning program. F.L.v.d.V. was supported by the E-rare project EURO-CMC. M.O. was supported by the NWO, 016.176.006). A.C. and C.C. were supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and the Fundacao para a Ciencia e Tecnologia (FCT) (IF/00735/2014 to A.C. and SFRH/BPD/96176/2013 to C. C.)

Host genetic signatures of susceptibility to fungal disease

Our relative inability to predict the development of fungal disease and its clinical outcome raises fundamental questions about its actual pathogenesis. Several clinical risk factors are described to predispose to fungal disease, particularly in immunocompromised and severely ill patients. However, these alone do not entirely explain why, under comparable clinical conditions, only some patients develop infection. Recent clinical and epidemiological studies have reported an expanding number of monogenic defects and common polymorphisms associated with fungal disease. By directly implicating genetic variation in the functional regulation of immune mediators and interacting pathways, these studies have provided critical insights into the human immunobiology of fungal disease. Most of the common genetic defects reported were described or suggested to impair fungal recognition by the innate immune system. Here, we review common genetic variation in pattern recognition receptors and its impact on the immune response against the two major fungal pathogens Candida albicans and Aspergillus fumigatus. In addition, we discuss potential strategies and opportunities for the clinical translation of genetic information in the field of medical mycology. These approaches are expected to transfigure current clinical practice by unleashing an unprecedented ability to personalize prophylaxis, therapy and monitoring for fungal disease.This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 to AC, and SFRH/BPD/96176/2013 to CC), the Institut Mérieux (Mérieux Research Grant 2017 to CC), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017 to AC)

The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives

This is the final version. Available on open access from Oxford University Press via the DOI in this recordCandida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients

Immunotherapeutic approaches to treatment of fungal diseases

Fungal infections cause morbidity worldwide and are associated with an unacceptably high mortality despite the availability of antifungal drugs. The incidence of mycoses is rising because of the HIV pandemic and because immunomodulatory drugs are increasingly used to treat autoimmune diseases and cancer. New classes of antifungal drugs have only been partly successful in improving the prognosis for patients with fungal infection. Adjunctive host-directed therapy is therefore believed to be the only option to further improve patient outcomes. Recent advances in the understanding of complex interactions between fungi and host have led to the design and exploration of novel therapeutic strategies in cytokine therapy, vaccines, and cellular immunotherapy, each of which might become viable adjuncts to existing antifungal regimens. In this report, we discuss immunotherapeutic approaches-the rationale behind their design, the challenges in their use, and the progress that is so urgently needed to overcome the devastating effect of fungal diseases

Author Correction: A guiding map for inflammation

Correction to: Nature Immunology https://doi.org/10.1038/ni.3790, published online 19 July 2017