Manipulation of host angioneogenesis

Abstract

Despite progress over the last decade, opportunistic mold infections continue to be associated with high rates of morbidity and mortality in immunocompromised patients. Given the propensity of molds to invade blood vessels, vasculopathy may be a barrier to effective delivery of antifungal drugs to infected tissue. In a recent study (Ben-Ami R et al. Blood, 2009), we found that A. fumigatus suppresses endothelial cell migration, differentiation and capillary tube formation both in vitro and in an animal model system. This effect is mediated by secreted secondary metabolites such as gliotoxin. Herein, I discuss the potential implications of how invasive molds modulate host angiogenesis in experimental and clinical mold infections. Strategies that employ reversal of vasculopathy, neutralization of metabolites that inhibit endothelial function, exploration of pro-angiogenic factors as diagnostic or prognostic markers affected patients will likely be the focus of future studies. This complex, yet emerging field might add another level of knowledge and therapeutic choices in the management of these devastated infections.

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Acknowledgements

I thank Russell E. Lewis for useful comments and assistance with figures. Supported in part by NIH RO3 AI083733-01.

Figures and Tables

Figure 1 A model for the potential role of Aspergillus secondary metbolites in modulating host angioneogenesis. The site of A. fumigatus infection is marked by a circular dashed line. Invasion of tissue and blood vessels by hyphae induce hypoxia and an inflammatory response. Hypoxia-inducible factor (HIF) and proinflammatory cytokines (e.g., IL-1) act as potent stimuli for angiogenesis by inducing VEGF gene expression. Fungal secondary metabolites, such as fumagillin (FUM) or gliotoxin (GLIO), counter the action of these transcription factors, and block VEGF gene expression. VEGF deficiency leads to endothelial cell apoptosis and suppresses new vessel formation, further attenuating perfusion of the infection site.

Figure 2 How does the secondary metabolite gliotoxin “tip the scale” in the pathogenesis of invasive aspergillosis in experiemental models?

Figure 3 Cutaneous model of aspergillosis for studying anti-angiogeneic effects of Aspergillus.