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.

Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation

“…In the first series of experiments, the depth of fungal invasion and degree of fungal burden were graded histologically over time posttransplant, as previously described (fig. S6) (13). The invasion correlated with increased tissue iron content as quantified by standard morphometric measurements with Prussian blue staining (33).…”

“…Tissue invasion is a more virulent presentation that often results in fatal airway anastomotic infections and invasive pulmonary aspergillosis in the lower respiratory tract (9, 14, 46, 49). We have previously shown that A. fumigatus growth is mostly invasive in progressive allograft rejection, whereas the infection results in airway colonization in syntransplants (13). Because all lung transplant recipients receive immunosuppressive therapy, however, immune suppression cannot explain on its own the switch from fungal colonization to invasive growth, and the responsible factors remain poorly understood.…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…The relative ischemia of the airway anastomosis is associated with a proclivity to infection, especially with Aspergillus and Pseudomonas. The OTT model appears to be a useful model for this process (79,80).…”

The novel globin protein fungoglobin is involved in low oxygen adaptation of Aspergillus fumigatus

“…Recent studies confirmed that reduced oxygen concentrations actually occur in the mammalian lung at sites of infection, and that tissue invasion by A. fumigatus is aggravated during progressive airway ischemia (Grahl et al, 2011;Hsu et al, 2013). Therefore, a better understanding of the fungal adaptation to O2 deprivation is considered as one prerequisite for the development of improved treatment options in the future.…”