Invasive aspergillosis (IA) is an important cause of respiratory and disseminated infection in immunocompromised patients, and the most common cause of infectious pneumonic mortality in recipients of hematopoietic stem cell transplants. Mortality from IA remains unacceptably high despite the availability of novel antifungal agents. The poor efficacy of antifungal drugs against IA may be linked to the propensity of Aspergillus species to invade pulmonary blood vessels, causing intravascular thrombosis, tissue ischemia and infarction. This vasculopathy sequesters infected tissue, thereby limiting the delivery of antifungal agents to the site of infection. Furthermore, IA is associated with down-regulation of the expression of genes encoding for important mediators of angiogenesis, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), suggesting that the vascular response to IA is suppressed. We hypothesize that therapeutic administration of pro-angiogenic growth factors together with antifungal drugs will increase the survival rate in experimental IA by increasing the tissue concentrations of the antifungal drugs.
In aim 1, we propose to assess the feasibility of treating IA with pro-angiogenic growth factors, alone or in combination with the antifungal drug amphotericin B (AMB). To that end, we will use two murine models of IA following induction of neutropenia with cyclophosphamide: (1) An acute pulmonary model, in which infection is established by intranasal instillation of a concentrated spore suspension;(2) A subacute model, in which myocutaneous infection is induced by subcutaneous injection of spore suspension. In each model, the following treatment groups will be assessed: VEGF, bFGF, VEGF plus bFGF, AMB, AMB plus VEGF, AMB plus bFGF, and AMB plus VEGF and bFGF. Two additional groups of mice will receive treatment with sunitinib, an inhibitor of angiogenesis, alone or in combination with AMB. Three types of endpoints will be assessed and compared among treatment groups: (1) Survival over a period of 7 days (pulmonary model only);(2) Tissue fungal burden, measured by quantitative polymerase chain reaction (qPCR);and (3) Angiogenesis at the site of infection, assessed in vivo in the myocutaneous model using the previously described matrigel assay, and in pulmonary tissue sections using microvessel density.
In aim 2, we will determine the effect of treatment with VEGF and bFGF on the tissue concentration of AMB. AMB concentrations will be measured in pulmonary tissue and in matrigel plugs using high performance liquid chromatography, and compared between groups of mice receiving AMB alone and groups receiving AMB plus VEGF and/or bFGF.

Public Health Relevance

Invasive aspergillosis is a major cause of sickness and death in patients with cancer and a weakened immune system. Despite the availability of new antifungal drugs and improved supportive care, mortality from these infections remains unacceptably high. We hypothesize that the occlusion of blood vessels in the course of invasive aspergillosis limits the penetration of antifungal drugs into infected tissue, and that treatment with growth factors that enhance the formation of new vessels might improve the outcome of this severe fungal infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI083733-02
Application #
7905095
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Duncan, Rory A
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$77,000
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lewis, Russell E; Georgiadou, Sarah P; Sampsonas, Fotis et al. (2014) Risk factors for early mortality in haematological malignancy patients with pulmonary mucormycosis. Mycoses 57:49-55
Georgiadou, S P; Sampsonas, F L; Rice, D et al. (2013) Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary cancer center is safe and reveals noncancerous, noninfectious entities as the most common diagnoses. Eur J Clin Microbiol Infect Dis 32:101-5
Georgiadou, Sarah P; Tarrand, Jeffrey; Sipsas, Nikolaos V et al. (2013) Candiduria in haematologic malignancy patients without a urinary catheter: nothing more than a frailty marker? Mycoses 56:311-4
Ben-Ami, Ronen; Albert, Nathaniel D; Lewis, Russell E et al. (2013) Proangiogenic growth factors potentiate in situ angiogenesis and enhance antifungal drug activity in murine invasive aspergillosis. J Infect Dis 207:1066-74
Georgiadou, Sarah P; Kontoyiannis, Dimitrios P (2012) Concurrent lung infections in patients with hematological malignancies and invasive pulmonary aspergillosis: how firm is the Aspergillus diagnosis? J Infect 65:262-8
Chitasombat, Maria N; Kofteridis, Diamantis P; Jiang, Ying et al. (2012) Rare opportunistic (non-Candida, non-Cryptococcus) yeast bloodstream infections in patients with cancer. J Infect 64:68-75
Sipsas, Nikolaos V; Kontoyiannis, Dimitrios P (2012) Invasive fungal infections in patients with cancer in the Intensive Care Unit. Int J Antimicrob Agents 39:464-71
Kontoyiannis, Dimitrios P (2010) Manipulation of host angioneogenesis: A critical link for understanding the pathogenesis of invasive mold infections? Virulence 1:192-6