Research Article: Human Genetic Susceptibility to Invasive Aspergillosis

Date Published: August 8, 2013

Publisher: Public Library of Science

Author(s): Cristina Cunha, Franco Aversa, Luigina Romani, Agostinho Carvalho, Joseph Heitman.

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

Abstract

Partial Text

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.

The physical barrier of the respiratory tract affords the first line of resistance against inhaled conidia of Aspergillus. In the event these escape the ciliated epithelium, conidia will then be challenged by cells of the innate immune system, including resident alveolar macrophages and dendritic cells (DCs), as well as recruited inflammatory cells, mainly polymorphonuclear neutrophils. These cells express a vast repertoire of pattern recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPs) and drive the secretion of proinflammatory cytokines and chemokines that arbitrate innate and adaptive immune responses. In the case of fungi, the cell wall is the main source of PAMPs owing to its dynamic composition and structural properties according to morphotype, growth stage, and environmental conditions [3]. Toll-like receptors (TLR)-2 (in cooperation with TLR1 and TLR6), TLR3, TLR4, and TLR9, and the C-type lectin receptors dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), mannose receptor, and dectin-1 are among the PRRs recognizing fungal PAMPs including mannan, β-glucan, and nucleic acids [4]. Fungal sensing is further assisted by the action of collectins, ficolins, pentraxins, and complement components that act as opsonins and facilitate the interaction of phagocytes with fungi. Mammalian PRRs are also able to respond to products released from damaged host cells, including nucleic acids and alarmin proteins, collectively known as danger-associated molecular patterns (DAMPs). The unexpected convergence of PAMP- and DAMP-mediated molecular pathways raised the question of whether and how the host discriminates between them and the relative involvement of either one in inflammation, immune homeostasis, and mechanisms of repair during 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].

The inborn deficiency of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to CGD is the best known example of primary immunodeficiency with predisposition to IA [7]. As a result of the impaired production of reactive oxygen species, patients with CGD often develop IA, typically within the first decade of life. Of interest, these patients are uniquely susceptible to diseases with the A. nidulans complex, which are weakly virulent molds that rarely cause infection in immunocompromised patients. For most individuals however, genetic propensity to aspergillosis has a polygenic source. A polygenic variant by itself has a negligible effect on phenotype; only in combination with other remarkable predisposing variants (e.g., profound immunosuppression) do sizeable phenotypic effects arise.

Our existing knowledge of the genetic bases of susceptibility to IA derives from studies screening single variants in candidate genes using small patient cohorts. In addition, statistical issues with multiple comparisons and the lack of validation in larger, independent cohorts or via biological studies of disease mechanisms are further limitations of candidate gene association studies. As cutting-edge “omics” techniques are becoming affordable, multidisciplinary integrative approaches targeting variability in genome-wide association studies or expression in whole-transcriptomics studies may help to identify novel susceptibility signatures in otherwise unsuspected genes or pathways besides confirming those currently acknowledged. As “omics” have contributed to the identification of genetic susceptibility traits in cancer research, these techniques could be ultimately extrapolated with success to the field of invasive fungal diseases. Furthermore, only now are we beginning to fully grasp the significance of the microbiota and its interactions with the mammalian immune system in defining susceptibility to infection. Indeed, the structure and composition of lung microbial communities in patients at-risk was found to diverge significantly from that of healthy individuals [24], thus suggesting a likely susceptibility signature to IA that may involve a host–fungus–microbiota triad. All these state-of-the-art approaches however do not weaken the weight of functional validation. Given that “omics” studies by nature disregard all preceding knowledge about disease pathobiology, studies unveiling useful mechanistic insights into the relevant signatures found, be them genetic or biological, are still essential.

The identification of patient-specific prognostic signatures of susceptibility to IA in high-risk patients is currently one major priority in the fields of hematology and microbiology. Ultimately, the discovery of reliable markers of susceptibility consistently associated with risk for IA and functionally correlated with impaired antifungal mechanisms of the host may be a turning point toward innovative stratification strategies based on genetic screening or immune profiling to predict risk and severity of disease, efficacy of antifungal prophylaxis and therapy, and eventually contribute to the successful design of antifungal vaccines.

 

Source:

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

 

0 0 vote
Article Rating
Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments