Human Genetic Susceptibility to Invasive Aspergillosis

Cristina Cunha,Agostinho Carvalho,Franco Aversa,Luigina Romani,Joseph Heitman

doi:10.1371/journal.ppat.1003434

Cristina Cunha, Agostinho Carvalho + Show 3 more

Open Access

https://doi.org/10.1371/journal.ppat.1003434

Copy DOI

Journal: PLoS Pathogens	Publication Date: Aug 8, 2013
Citations: 78	License type: CC BY 4.0

Affiliation: University of Perugia, University of Parma

Abstract

Aspergillosis includes a wide spectrum of diseases caused by fungi of the genus Aspergillus with clinical manifestations that range from colonization (e.g., aspergilloma), to allergic bronchopulmonary aspergillosis, to disseminated forms of infection. Invasive aspergillosis (IA) has been estimated to occur in 10% of acute myeloid leukemia patients during post-induction aplasia or consolidation therapy and after 5–15% of allogeneic hematopoietic stem cell transplants (HSCT) [1], [2]. Additional persons at risk for IA include recipients of solid organ transplants and patients with chronic granulomatous disease (CGD). Despite the significant progress attained in the management of this severe infection, its prevention, diagnosis, and therapy remain extremely difficult, rendering it a leading cause of death among immunocompromised patients. Additionally, concerns over antimold prescription and the remarkably high healthcare costs owing to its chronic course and mortality rates have been diverting clinicians from universal prophylaxis to risk stratification and preemptive approaches. This has inspired the search for novel individual prognostic factors, particularly genetic, to apply in the categorization of those most vulnerable to infection.

Highlights

Aspergillosis includes a wide spectrum of diseases caused by fungi of the genus Aspergillus with clinical manifestations that range from colonization, to allergic bronchopulmonary aspergillosis, to disseminated forms of infection
Recent evidence has demonstrated that the immune system distinguishes fungus- and danger-induced immune responses, a mechanism relying on the spatiotemporal regulation of Toll-like receptors (TLR) and the receptor for advanced glycation endproducts (RAGE) by the S100B alarmin [5]
The inborn deficiency of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to chronic granulomatous disease (CGD) is the best known example of primary immunodeficiency with predisposition to Invasive aspergillosis (IA) [7]

Summary

Introduction

Aspergillosis includes a wide spectrum of diseases caused by fungi of the genus Aspergillus with clinical manifestations that range from colonization (e.g., aspergilloma), to allergic bronchopulmonary aspergillosis, to disseminated forms of infection. Recent evidence has demonstrated that the immune system distinguishes fungus- and danger-induced immune responses, a mechanism relying on the spatiotemporal regulation of TLRs and the receptor for advanced glycation endproducts (RAGE) by the S100B alarmin [5] Despite their undisputed relevance to pathogen resistance, innate immune mechanisms of pathogen detection may behave as double-edged swords, becoming detrimental as the result of hyperproduction of proinflammatory cytokines facilitating tissue damage or impairing protective immunity. This may explain why neutrophils, indispensable in the implementation of the acute inflammatory response, may instead hamper resolution of infection through an excessive release of oxidants and proteases that may injure organs and promote fungal sepsis. The ability of Aspergillus to adapt to hypoxic microenvironments has been found to involve modifications in fungal metabolism leading to the production of secondary metabolites that promote lung inflammation, exacerbate infection, and influence subsequent host immune responses [6]

Genetic Variability of the Host and Susceptibility to IA

Amino acid change

Findings

Concluding Remarks