Therapeutic targeting the host hypoxia-response pathway to treat Mucormycosis

University Of Maryland Baltimore, Baltimore MD

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Mucormycosis is a deadly invasive infection caused by several fungal species belonging to the order Mucorales. The major risk factors include uncontrolled diabetes mellitus that results in hyperglycemia and ketoacidosis (DKA), other forms of acidosis, treatment with corticosteroids, solid organ or bone marrow transplantation, neutropenia, trauma and burns (e.g., wounded soldiers in Iraq and Afghanistan), malignant haematological disorders and deferoxamine therapy in patients receiving haemodialysis. The infection is generally acquired by inhalation of spores that are ubiquitous in nature and cause either rhino-orbital (almost exclusively in DKA patients) or pulmonary (mainly in neutropenic leukemic patients) disease. The treatment options for Mucormycosis are limited. There are currently no vaccines and only two antifungal agents approved by the USA FDA to treat this disease. The first is Amphotericin B (AmB) which has serious adverse effects, including nephrotoxicity, and very limited clinical success. Isavuconazole was recently approved to treat mucormycosis but it is not superior to AmB treatment. In the absence of surgical removal of the infected focus, antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose antifungal therapy, the mortality associated with mucormycosis is >50%. In patients with prolonged neutropenia or disseminated disease, mortality is 90-100%. Furthermore, since there are no federal requirements to report fungal infections, the true prevalence of mucormycosis is likely to be much higher than currently reported. The unacceptably high mortality rate, limited options for therapy and the extreme morbidity of highly disfiguring surgical therapy make it imperative to look for alternative strategies to treat and prevent mucormycosis. Our preliminary data suggests that Mucorales fungi engage the host cell hypoxia-response pathway in order to invade host tissue through the pulmonary epithelium. Specifically, inhibition of this pathway blocks fungal invasion and increases survival in a mouse model of mucormycosis. In Aim 1, we will examine the role of ANGPTL4, a high priority downstream effector molecule of this pathway, in the pathogenesis of mucormycosis and explore the therapeutic potential of blocking the action of this protein. In Aim 2 we will use single cell RNA-seq to identify downstream transcriptional targets of this pathway that are expressed during Mucorales infection in lung epithelial cells in vivo. We will then characterize the role of these targets in the context of Mucorales infection both in vitro and in vivo. In Aim 3, we will evaluate the effectiveness of the novel pathway targets as adjunctive therapy with antifungal agents in treating mucormycosis. We will use our clinically relevant murine models to evaluate the efficacy of various agents and modalities, alone and in combination with current antifungals, to treat mucormycosis. The ultimate goal of the work proposed here is to develop novel anti-infective strategies to disrupt molecular interactions that are important for disease progression of pulmonary mucormycosis.