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Aspergillus fumigatus invasion increases with progressive airway ischemia.

ABSTRACT: Despite the prevalence of Aspergillus-related disease in immune suppressed lung transplant patients, little is known of the host-pathogen interaction. Because of the mould's angiotropic nature and because of its capacity to thrive in hypoxic conditions, we hypothesized that the degree of Aspergillus invasion would increase with progressive rejection-mediated ischemia of the allograft. To study this relationship, we utilized a novel orthotopic tracheal transplant model of Aspergillus infection, in which it was possible to assess the effects of tissue hypoxia and ischemia on airway infectivity. Laser Doppler flowmetry and FITC-lectin were used to determine blood perfusion, and a fiber optic microsensor was used to measure airway tissue oxygen tension. Fungal burden and depth of invasion were graded using histopathology. We demonstrated a high efficacy (80%) for producing a localized fungal tracheal infection with the majority of infection occurring at the donor-recipient anastomosis; Aspergillus was more invasive in allogeneic compared to syngeneic groups. During the study period, the overall kinetics of both non-infected and infected allografts was similar, demonstrating a progressive loss of perfusion and oxygenation, which reached a nadir by days 10-12 post-transplantation. The extent of Aspergillus invasion directly correlated with the degree of graft hypoxia and ischemia. Compared to the midtrachea, the donor-recipient anastomotic site exhibited lower perfusion and more invasive disease; a finding consistent with clinical experience. For the first time, we identify ischemia as a putative risk factor for Aspergillus invasion. Therapeutic approaches focused on preserving vascular health may play an important role in limiting Aspergillus infections.

SUBMITTER: Hsu JL

PROVIDER: S-EPMC3796538 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Aspergillus fumigatus invasion increases with progressive airway ischemia.

Hsu Joe L JL Khan Mohammad A MA Sobel Raymond A RA Jiang Xinguo X Clemons Karl V KV Nguyen Tom T TT Stevens David A DA Martinez Marife M Nicolls Mark R MR

PloS one 20131014 10

Despite the prevalence of Aspergillus-related disease in immune suppressed lung transplant patients, little is known of the host-pathogen interaction. Because of the mould's angiotropic nature and because of its capacity to thrive in hypoxic conditions, we hypothesized that the degree of Aspergillus invasion would increase with progressive rejection-mediated ischemia of the allograft. To study this relationship, we utilized a novel orthotopic tracheal transplant model of Aspergillus infection, i ...[more]

PMID: 24155924

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Project description:Invasive aspergillosis is initiated when Aspergillus fumigatus adheres to and invades the pulmonary epithelial cells that line the airways and alveoli. To gain deeper insight into how pulmonary epithelial cells respond to A. fumigatus invasion, we used transcriptome sequencing (RNA-seq) to determine the transcriptional response of the A549 type II alveolar epithelial cell line to infection with strains CEA10 and Af293, two clinical isolates of A. fumigatus. Upstream regulator analysis of the data indicated that while both strains activated virtually identical host cell signaling pathways after 16 h of infection, only strain CEA10 activated these pathways after 6 h of infection. Many of the pathways that were predicted to be activated by A. fumigatus, including the tumor necrosis factor (TNF), interleukin-1α (IL-1α), IL-1β, IL-17A, Toll-like receptor 2 (TLR2), and TLR4 pathways, are known to be critical for the host defense against this fungus. We also found that the platelet-derived growth factor BB (PDGF BB) and progesterone receptor (PGR) pathways were activated by A. fumigatus. Using pharmacologic inhibitors, we determined that blocking the PDGF receptor or PGR inhibited the endocytosis of both strains of A. fumigatus in an additive manner. Both the PDGF BB and PGR pathways are also predicted to be activated by infection of A549 cells with other molds, such as Rhizopus delemar and Rhizopus oryzae. Thus, these pathways may represent a common response of pulmonary epithelial cells to mold infection. IMPORTANCE Invasive aspergillosis is a deadly invasive fungal infection that initiates when Aspergillus fumigatus spores are inhaled and come into contact with the epithelial cells that line the airways and alveoli. Understanding this fungus-host interaction is important for the development of novel therapeutics. To gain a deeper understanding of how these airway epithelial cells respond to A. fumigatus during infection, we used RNA-seq to determine the transcriptional response of alveolar epithelial cells to infection with two different clinical isolates of A. fumigatus. Our analysis identified new host response pathways that have not previously been tied to infection with A. fumigatus. Pharmacological inhibition of two of these pathways inhibited the ability of A. fumigatus to invade airway epithelial cells. These two pathways are also predicted to be activated by infection with other filamentous fungi. Thus, these pathways may represent a common response of alveolar epithelial cells to mold infection.

Project description:Germination from conidia to hyphae and hyphal propagation of Aspergillus fumigatus are the key pathogenic steps in the development of invasive pulmonary aspergillosis (IPA). By applying in vitro observations in a clinical study of 13 patients diagnosed with probable IPA, here, we show that the transition from colonization to the A. fumigatus invasive stage is accompanied by the secretion of triacetylfusarinine C (TafC), triacetylfusarinine B (TafB), and ferricrocin (Fc) siderophores into urine, with strikingly better sensitivity performance than serum sampling. The best-performing index, the TafC/creatinine index, with a median value of 17.2, provided 92.3% detection sensitivity (95% confidence interval [CI], 64.0 to 99.8%) and 100% specificity (95% CI, 84.6 to 100%), i.e., substantially better than the corresponding indications provided by galactomannan (GM) and β-d-glucan (BDG) serology. For the same patient cohort, the serum GM and BDG sensitivities were 46.2 and 76.9%, respectively, and their specificities were 86.4 and 63.6%, respectively. The time-dependent specific appearance of siderophores in the host's urine represents an impactful clinical diagnostic advantage in the early discrimination of invasive aspergillosis from colonization. A favorable concentration of TafC in a clinical specimen distant from a deep infection site enables the noninvasive sampling of patients suffering from IPA. IMPORTANCE The importance of this research lies in the demonstration that siderophore analysis can distinguish between asymptomatic colonization and invasive pulmonary aspergillosis. We found clear associations between phases of fungal development, from conidial germination to the proliferative stage of invasive aspergillosis, and changes in secondary metabolite secretion. The critical extracellular fungal metabolites triacetylfusarinines C and B are produced during the polarized germination or postpolarized growth phase and reflect the morphological status of the proliferating pathogen. False positivity in Aspergillus diagnostics is minimized as mammalian cells do not synthesize Aspergillus siderophore or mycotoxin molecules.

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Aspergillus fumigatus invasion increases with progressive airway ischemia.

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Aspergillus fumigatus invasion increases with progressive airway ischemia.

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