Manipulation of host angioneogenesis

Kontoyiannis, Dimitrios P.

doi:10.4161/viru.1.3.11380

Cited by 12 publications

(5 citation statements)

References 20 publications

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“…To date, the literature hypothesizes that the mould itself drives angioinvasion [25], whereas the results of our study suggest that, in fact, the mould is responding to its microenvironment. Although the current study cannot unequivocally delineate the differential impact of the host or the pathogen, the overall perfusion kinetics in the Doppler flowmetry and FITC-lectin studies of both infected and non-infected allografts were similar.…”

Section: Discussioncontrasting

confidence: 67%

“…As predicted by our model, in these patients A. fumigatus typically displays a non-invasive phenotype. For a patient with COPD, in addition to architectural destruction, there is a slowly progressive destruction of the microvasculature and down regulation of VEGF [25,29]; in these patients a more indolent invasive infection may occur, chronic necrotizing aspergillosis. For lung transplant patients, ischemia due to the failure to restore the bronchial circulation may result in tracheal anastomotic infections early, and later, with Aspergillus colonization and with progressive microvascular loss associated with chronic rejection, in the development of IPA.…”

Section: Discussionmentioning

confidence: 99%

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Aspergillus fumigatus Invasion Increases with Progressive Airway Ischemia

et al. 2013

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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.

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Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatus Invasion Increases with Progressive Airway Ischemia

et al. 2013

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“…fumigatus invasion. Although the role of HIF in fungal pathogenesis is not well described, HIF plays a key role in mitigating bacterial pathogenesis [42, 43]. For instance, the downregulation of HIF-1α by Chlamydia is thought to provide a virulence advantage for the organism [43].…”

Section: Discussionmentioning

confidence: 99%

Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus

et al. 2013

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Microvascular ischemia and infections are associated with the development of chronic rejection following lung transplantation. The von Hippel–Lindau protein (VHL) controls protein levels of hypoxia-inducible factors (HIFs), regulates vascular repair, and improves tissue perfusion. Here, we studied the role of VHL in microvascular repair by orthotopically transplanting tracheas into mice with VHL haplodeficiency in Tie2 lineage cells. We showed that VHL haplodeficiency prolonged airway microvascular perfusion and promoted tissue blood flow through the production of the angiogenic factors, SDF-1 and angiopoietin 1. VHL-haplodeficient pulmonary endothelial cells exhibited increased angiogenic activity, resistance to serum deprivation-induced cell death, and enhanced microvascular repair. By contrast, in recipient mice with HIF-1α deficiency in Tie2 lineage cells, microvascular repair was significantly diminished and suggested that recipient-derived HIF-1α normally participates in the repair of alloimmune-mediated microvascular damage. To evaluate the translational impact of our findings, we compared VHL-haplodeficient mice with wild-type controls using a model of Aspergillus airway infection. In 83 % of the VHL-haplodeficient recipients, Aspergillus fumigatus was noninvasive in contrast to 75 % of wild-type mice in which the mold was deeply invasive. Our study demonstrated that stabilization of HIF-1α in angiogenic cells, through Tie2 cell VHL haplodeficiency, promoted airway microvascular regeneration and vascular normalization and thereby minimized tissue ischemia and hypoxia. By also mitigating the virulence of A. fumigatus, a common pathogen and itself a risk factor for the development of lung transplant rejection, the selective enhancement of HIF-1α expression has the prospect of offering several novel therapeutic effects to transplant recipients.Key messageMicrovascular loss and prolonged ischemia occurs with acute rejection.Von Hippel-Lindau (VHL) protein controls hypoxia inducible factors (HIFs).In tracheal allografts, VHL haplodeficient Tie2 cells promote neovascularization.Reduced transplant ischemia limits Aspergillus invasion.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-013-1063-8) contains supplementary material, which is available to authorized users.

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“…Gene expression profiling in human monocytes and in immunocompromised mice infected with Rhizopus versus Aspergillus demonstrates a differential induction of immune-related genes during mucormycosis [ 52 ], which likely reflects unique virulence traits of Mucorales species. Similarly, transcriptional profiling at early time points of infection in wild-type fruit flies infected with Rhizopus (pathogenic) versus Aspergillus (nonpathogenic) indicated distinct sets of genes that were selectively regulated in response to mucormycosis [ 23 ].…”

Section: Virulence Studies Of Filamentous Fungi mentioning

confidence: 99%

Recent Advances in the Use ofDrosophila melanogasteras a Model to Study Immunopathogenesis of Medically Important Filamentous Fungi

Hamilos

Samonis

Kontoyiannis³

2012

International Journal of Microbiology

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Airborne opportunistic fungi, including Aspergillus and other less common saprophytic molds, have recently emerged as important causes of mortality in immunocompromised individuals. Understanding the molecular mechanisms of host-fungal interplay in robust experimental pathosystems is becoming a research priority for development of novel therapeutics to combat these devastating infections. Over the past decade, invertebrate hosts with evolutionarily conserved innate immune signaling pathways and powerful genetics, such as Drosophila melanogaster, have been employed as a means to overcome logistic restrains associated with the use mammalian models of fungal infections. Recent studies in Drosophila models of filamentous fungi demonstrated that several genes implicated in fungal virulence in mammals also play a similarly important pathogenic role in fruit flies, and important host-related aspects in fungal pathogenesis are evolutionarily conserved. In view of recent advances in Drosophila genetics, fruit flies will become an invaluable surrogate model to study immunopathogenesis of fungal diseases.

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Manipulation of host angioneogenesis

Cited by 12 publications

References 20 publications

Aspergillus fumigatus Invasion Increases with Progressive Airway Ischemia

Aspergillus fumigatus Invasion Increases with Progressive Airway Ischemia

Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus

Recent Advances in the Use ofDrosophila melanogasteras a Model to Study Immunopathogenesis of Medically Important Filamentous Fungi

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