Toward the Identification of a Genetic Risk Signature for Pulmonary Aspergillosis in Chronic Obstructive Pulmonary Disease

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A . fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP 51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP 51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A . fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A . fumigatus . This review paper comprehensively discusses the current clinical challenges caused by A . fumigatus and provides insights on how to address them.

show abstract

“…2015 , Wojtowicz et al. 2015 ), as well as in patients with chronic obstructive pulmonary disease ( Cunha & Carvalho 2018 , He et al. 2018 ).…”

Section: Virulence Immunology and Pathogenesis Of Aspergillusmentioning

confidence: 99%

Aspergillus fumigatusand aspergillosis: From basics to clinics

Arastehfar

Carvalho

Houbraken

et al. 2021

Studies in Mycology

158

112

View full text Add to dashboard Cite

show abstract

“…71 This association was validated in a large, independent study 35 and extended across different clinical settings, including solid organ transplant recipients 72,73 and patients with chronic obstructive pulmonary disease. 74,75 Taken together, these studies disclose genetic variants in PTX3 as the most robust genetic markers for IPA identified to date. Mechanistically, PTX3 deficiency was found to hamper the normal alveolar expression of the protein, and, at a cellular level, it impaired the antifungal effector mechanisms of neutrophils.…”

Section: Defects Of Soluble Pattern Recognition Receptorsmentioning

confidence: 63%

Genetic defects in fungal recognition and susceptibility to invasive pulmonary aspergillosis

Cunha

Carvalho

2019

Medical Mycology

Self Cite

View full text Add to dashboard Cite

The interindividual variability in the onset and clinical course of invasive pulmonary aspergillosis (IPA) raises fundamental questions about its actual pathogenesis. Clinical and epidemiological studies have reported only a few examples of monogenic defects, however an expanding number of common polymorphisms associated with IPA has been identified. Understanding how genetic variation regulates the immune response to Aspergillus provides critical insights into the human immunobiology of IPA by pinpointing directly relevant immune molecules and interacting pathways. Most of the genetic defects reported to increase susceptibility to infection were described or suggested to impair fungal recognition by the innate immune system. In this review, we discuss the contribution of host genetic variation in pattern recognition receptors to the development of IPA. An improved understanding of the molecular and cellular processes that regulate human susceptibility to IPA is ultimately expected to pave the way toward personalized medical interventions based on host-directed risk stratification and individualized immunotherapy.

show abstract

“…Remarkably, and according to its nonredundant role in immunity to A. fumigatus in mouse models of infection (Garlanda et al 2002), genetic variation in PTX3 was identified as a major risk factor for IPA after HSCT (Cunha et al 2014). These findings were validated in a large, independent study (Fisher et al 2017) and extended across different clinical settings, including solid organ transplant recipients (Cunha et al 2015;Wojtowicz et al 2015) and patients with chronic obstructive pulmonary disease (Cunha and Carvalho 2018;He et al 2018). Collectively, these studies highlight genetic variation in PTX3 as robust host-derived markers for IPA and lay the foundations for well-designed clinical trials assessing their validity in the clinical setting.…”

Section: Soluble Pattern Recognition Receptorsmentioning

confidence: 92%

Host Genetic Signatures of Susceptibility to Fungal Disease

Campos

Veerdonk

Gonçalves

et al. 2018

Fungal Physiology and Immunopathogenesis

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Toward the Identification of a Genetic Risk Signature for Pulmonary Aspergillosis in Chronic Obstructive Pulmonary Disease

Cited by 7 publications

References 10 publications

Aspergillus fumigatusand aspergillosis: From basics to clinics

Aspergillus fumigatusand aspergillosis: From basics to clinics

Genetic defects in fungal recognition and susceptibility to invasive pulmonary aspergillosis

Host Genetic Signatures of Susceptibility to Fungal Disease

Contact Info

Product

Resources

About