Genetic defects in fungal recognition and susceptibility to invasive pulmonary aspergillosis

Cunha, Cristina; Carvalho, Agostinho

doi:10.1093/mmy/myy057

Cited by 18 publications

(24 citation statements)

References 92 publications

(103 reference statements)

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“…In an era of extensive iatrogenic immunosuppression, the pharmaceutical pipeline for development of novel antifungal drugs is running dry, and new therapies are needed that are possibly based on a better understanding of the host/pathogen interplay in the pathogenesis of aspergillosis. In this regard, genetic data from the clinic, traditionally translated into risk stratification and diagnostic strategies, might assist in developing original applications of available therapies (including those targeting complement components, which are nowadays experiencing a renaissance [180]), and in the design and interpretation of clinical trials [161]. Furthermore, it is timely to address fundamental mechanisms of the antifungal immunity, which are expected to provide information on novel molecular targets for pharmacological intervention, thus paving the way to new and much urgent translational efforts in the field.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it is timely to address fundamental mechanisms of the antifungal immunity, which are expected to provide information on novel molecular targets for pharmacological intervention, thus paving the way to new and much urgent translational efforts in the field. In this regard, further exploitation of the interplay between PTX3 (currently, the best genetic marker for IPA [161]), the AP [25], and TLRs [148] holds promise to deliver new genetic and mechanistic tools for a more effective handling of A. fumigatus infections.…”

Section: Discussionmentioning

confidence: 99%

“…Onset and progression of aspergillosis are characterized by significant interindividual variability, which highlights the relevance of heritable factors in determining human susceptibility to this infection. In this regard, while only a few monogenic defects have been identified that predispose to IPA, the body of common polymorphisms associated to the disease is steadily increasing and mostly comprises genes of the PRR and PRM families, including complement proteins and pentraxins [161].…”

Section: Genetic Variation In Human Complement and Pentraxin Genes Anmentioning

confidence: 99%

“…Based on available clinical information, genetic variation in PTX3 is 'the most robust genetic marker for IPA identified to date' [161]. Furthermore, the therapeutic efficacy of the protein in several animal models of aspergillosis, and its additive and/or synergistic effects on established antifungal drugs (as discussed above) strongly encourage the translation of this long pentraxin to the clinic, for prophylaxis and/or treatment of IA, either alone or in the combination therapy.…”

Section: Genetic Variation In Human Complement and Pentraxin Genes Anmentioning

confidence: 99%

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The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

et al. 2020

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Aspergillosis is a life-threatening infection mostly affecting immunocompromised individuals and primarily caused by the saprophytic fungus Aspergillus fumigatus. At the host-pathogen interface, both cellular and humoral components of the innate immune system are increasingly acknowledged as essential players in the recognition and disposal of this opportunistic mold. Fundamental hereof is the contribution of the complement system, which deploys all three activation pathways in the battle against A. fumigatus, and functionally cooperates with other soluble pattern recognition molecules, including pentraxins. In particular, preclinical and clinical observations point to the long pentraxin PTX3 as a nonredundant and complement-dependent effector with protective functions against A. fumigatus.Based on past and current literature, here we discuss how the complement participates in the immune response to this fungal pathogen, and illustrate its crosstalk with the pentraxins, with a focus on PTX3. Emphasis is placed on the molecular mechanisms underlying such processes, the genetic evidence from human epidemiology, and the translational potential of the currently available knowledge.Aspergillus fumigatus is an evolutionary ancient filamentous fungus (mold) that flourishes in soil and decomposing vegetation [1]. Traditionally regarded as asexual, the life cycle of this ubiquitous saprophyte actually comprises cryptic forms of sexual reproduction [2] and is hallmarked by several morphotypes with distinct metabolic, compositional, and structural traits [3]. The metabolically inactive and asexual airborne spores (known as dormant or resting conidia) are encased in a robust cell wall mostly made of complex polysaccharides [i.e., aand b-glucans, chitin, galactomannan (GM), and galactosaminogalactan (GAG)] in addition to lipids, proteins, and melanin pigments [i.e., dihydroxynaphthalene (DHN) melanin] [4]. Small in size (i.e., 2-3 µm across) and enveloped in a layer of hydrophobic rodlet-like proteins (i.e.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Genetic Variation In Human Complement and Pentraxin Genes Anmentioning

confidence: 99%

Section: Genetic Variation In Human Complement and Pentraxin Genes Anmentioning

confidence: 99%

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The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

et al. 2020

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“…Hence, any change in these genes could impair normal host immune response, leading to devastating fungal infection [21,51]. Several genetic polymorphisms have been found to be associated with increased risk for IA, e.g., DECTIN-1, DC-SIGN, TLR4, IL10, S100B, PTX3, PLG, IFNG, and TNFR1 [15,35,52]. However, these proteins have mainly been identified in North America and Europe, except for a single study in South Korea [24].…”

Section: Discussionmentioning

confidence: 99%

Genetic Risk Surveillance for Invasive Aspergillosis in Hematology Patients: A Prospective Observational Study

et al. 2020

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Introduction: The association between genetic background and the risk of invasive aspergillosis (IA) has not been addressed in Thailand. We conducted genetic risk surveillance for IA among Thai hematologic patients. Methods: We conducted a prospective observational cohort study including moderate-to high-risk hematology patients at Ramathibodi Hospital. IA occurrence, relevant clinical data, and genetic analyses were assessed. Odds ratios (ORs) of IA were assessed for the presence of the selected single nucleotide polymorphism genotype using logistic regression. Results: A total of 357 patients were enrolled. The most common hematologic disease was non-Hodgkin lymphoma (45.1%). IA was diagnosed in 36 patients (10.10%). The C allele of IL10 rs1800896 was associated with an increased risk of IA (adjusted OR 5.297; 95% confidence interval [CI] 2.032-13.809, p = 0.001). In multivariate Cox regression analysis, prolonged neutropenia and the C allele of IL10 rs1800896 were associated with IA (hazard ratio [HR] 12.585; 95% CI 3.866-40.967, p \ 0.001 and HR 2.449; 95% CI 1.097-5.468, p = 0.042, respectively). Conclusions: Carrying the C allele of IL10 rs1800896 was associated with an increased risk of IA among moderate-to high-risk Thai patients with hematologic diseases. This finding can potentially lead to a novel risk stratification scheme to further prevent IA in resource-limited settings.

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Genetic Regulation of the Host-Fungus Interaction in the Pathogenesis of Aspergillosis

Antunes

Cunha

Carvalho

2019

Curr Fungal Infect Rep

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Purpose of Review There is significant interindividual variability in the development and progression of fungal diseases, most notably invasive pulmonary aspergillosis (IPA). The integration of individual traits into clinically valid procedures to predict the risk and progression of infection, and the efficacy of antifungal prophylaxis and therapy, will change the current healthcare landscape regarding the management of patients at risk of IPA and, likely, other fungal infections. Recent Findings Over the last decade, an expanding number of common polymorphisms associated with IPA have been reported, adding to the information available on monogenic defects underlying severe forms of the disease. Predisposition to IPA is therefore nowadays considered to result from a combination of clinical and host factors, with the latter being most likely regulated at the genetic level. Summary In this review, we address the contribution of the genetic profile of the host to the outcome of the host-fungus interaction and discuss the application of this information in potential strategies with the aim of moving towards personalized prognostics, diagnostics, and treatment.

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Genetic defects in fungal recognition and susceptibility to invasive pulmonary aspergillosis

Cited by 18 publications

References 92 publications

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

Genetic Risk Surveillance for Invasive Aspergillosis in Hematology Patients: A Prospective Observational Study

Genetic Regulation of the Host-Fungus Interaction in the Pathogenesis of Aspergillosis

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