Implications of hypoxic microenvironments during invasive aspergillosis

Abstract

Summary In order to cause disease, all pathogens must tolerate microenvironmental stresses encountered in vivo during infection. One microenvironmental stress that is known to occur at sites of tissue damage is hypoxia. Yet, the occurrence and impact of hypoxic microenvironments during invasive aspergillosis, caused by the mold Aspergillus fumigatus, are essentially unknown. Here, we briefly review the potential implications of hypoxic microenvironments on the Aspergillus – host interaction. We focus on three areas where hypoxia may play a role in determining the outcome of infection: fungal virulence, host immune responses, and efficacy of current antifungal drug treatments.

Posaconazole-Loaded Leukocytes as a Novel Treatment Strategy Targeting Invasive Pulmonary Aspergillosis

“…Although a number of antifungals are available with excellent in vitro activity against A. fumigatus, their efficacy in vivo has been suboptimal. One contributing factor to this observation is that necrotic tissue surrounding pulmonary fungal lesions serves as a barrier to antifungal penetration, limiting the efficacy of these agents (7,8,168).…”

“…The hallmark pathophysiological features of established IPA such as tissue infarction, vascular coagulation, and necrosis that create a favourable microenvironment for the invading fungus, can also serve as a barrier to antifungal penetration. Impaired penetration of antifungal agents at the site of infection may explain treatment failure when dealing with fungi that are susceptible to the antifungal agent being administered (6)(7)(8). This hypothesis is supported by studies of intrapulmonary amphotericin B levels in a patient with IPA.…”

“…However, the necrotic and thrombotic tissue surrounding pulmonary fungal lesions provides a barrier to antifungal penetration and can reduce the efficacy of these drugs (6)(7)(8). The broad-spectrum antifungal agent posaconazole exhibits highly lipophilic physicochemical properties, which mediate its accumulation to high levels within cellular membranes.…”

“…Infarcted and necrotic tissue surrounding pulmonary fungal lesions provides a barrier to antifungal penetration, significantly undermining the clinical efficacy of antifungal drugs (6)(7)(8)168). …”

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

“…It has been shown that inflammation of the lung causes extensive tissue destruction that leads to hypoxic conditions (51,52). In addition, hypoxia can alter the efficacy of antifungal drugs on Aspergillus, causing an increase in the inhibition by amphotericin B, micafungin, and anidulafungin, a slight decrease in the efficacy of itraconazole, and no effect on voriconazole (53). The effectiveness of azoles is reduced under hypoxic conditions due to the reduction in ergosterol biosynthesis, which is one of the pathways more dependent on partial O 2 pressure (pO 2 ).…”