Abstract
Aspergillus is the causative agent of human diseases ranging from asthma to invasive infection. Genetic and environmental factors are crucial in regulating the interaction between the host and Aspergillus. The role played by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the first and rate-limiting step of tryptophan catabolism along the kynurenine pathway, is increasingly being recognized, but whether and how genetic variation of IDO1 influences the risk of aspergillosis in susceptible patients is incompletely understood. In addition, whether the closely related protein IDO2 plays a similar role remains unexplored. In the present study, we performed genetic association studies in two different cohorts of susceptible patients [cystic fibrosis (CF) patients and recipients of hematopoietic stem cell transplantation (HSCT)], and identified IDO1 polymorphisms that associate with the risk of infection in both cohorts. By using human bronchial epithelial cells and PBMC from CF and HSCT patients, respectively, we could show that the IDO1 polymorphisms appeared to down-modulate IDO1 expression and function in response to IFNγ or Aspergillus conidia, and to associate with an increased inflammatory response. In contrast, IDO2 polymorphisms, including variants known to profoundly affect protein expression and function, were differently associated with the risk of aspergillosis in the two cohorts of patients as no association was found in CF patients as opposed to recipients of HSCT. By resorting to a murine model of bone marrow transplantation, we could show that the absence of IDO2 more severely affected fungal burden and lung pathology upon infection with Aspergillus as compared to IDO1, and this effect appeared to be linked to a deficit in the antifungal effector phagocytic activity. Thus, our study confirms and extends the role of IDO1 in the response to Aspergillus, and shed light on the possible involvement of IDO2 in specific clinical settings.
Highlights
Aspergillus species are environmental fungi to which humans are constantly exposed and the inability to properly control the invasion results in a wide spectrum of diseases, ranging from asthma to the more severe and life-threatening invasive aspergillosis (IA) [1]
The eight tagSNPs encompassing IDO1/IDO2 loci have been successfully genotyped in the CF cohort with genotyping rate above 90%, not showing significant deviation from Hardy-Weinberg Equilibrium (HWE) and having Minor Allele Frequency (MAF) comparable to the ones reported for the European population of the 1,000 Genomes Consortium [26] (Supplementary Table 1)
Linkage disequilibrium (LD) analysis of the tagSNPs revealed the existence of two Linkage Disequilibrium (LD) blocks of 11 and 7 kb, respectively, with the first one spanning from the 5′-end to the 4th intron of IDO1 locus, and the second one ranging from the last intron of IDO1 to the first intron of IDO2 (Figure 1)
Summary
Aspergillus species are environmental fungi to which humans are constantly exposed and the inability to properly control the invasion results in a wide spectrum of diseases, ranging from asthma to the more severe and life-threatening invasive aspergillosis (IA) [1]. The host immune response as well as the degree of exposure are critical determinants for the development of infection and gauge the clinical manifestations of aspergillosis. Specific diseases and/or clinical conditions unbalance the immune response to Aspergillus and favor the development of characteristic fungal infections. One such example is represented by cystic fibrosis (CF, OMIM#219700), an autosomal recessive disorder caused by mutations in the gene encoding for the Cystic Fibrosis transmembrane conductance regulator Severe IA occur in severely immunocompromised patients such as those diagnosed with acute leukemia and chronic lymphoproliferative disorders, or recipients of allogeneic hematopoietic stem cell and solid-organ transplants [4]
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