Kieren Marr, M.D.

Phone: (206)667-2995
Fax: (206) 667-4411
E-mail: kmarr@fhcrc.org

CURRENT RESEARCH INTERESTS

Fungal diseases

Aspergillus fumigatus is a filamentous fungus that currently accounts for a large number of infection-related deaths in immunocompromised patients. Laboratory and clinical studies are being performed to achieve the overall goal of developing therapeutic strategies to prevent filamentous fungal infections.

Inflammatory Responses to Aspergillus fumigatus.

The pulmonary response to inhaled Aspergillus fumigatus is mediated by the alveolar macrophage, which ingests and kills conidia before the spores have a chance to mature into hyphae. Macrophages coordinate secondary responses through mechanisms that include secretion of cytokines and chemokines, whilst dendritic cells (DCs) coordinate CD4+ T lymphocyte responses. Recent studies have implicated Toll-like receptors in mediating multiple functions of innate and adaptive immunity, both by triggering macrophage secretion of soluble factors and by inducing DC maturation. Our studies indicate that A. fumigatus hyphal products stimulate macrophages to produce TNF-a, and induce DCs to mature and prime Th1-type CD4+ T cells more than conidial products. Murine macrophage cytokine secretion occurs independent of the pathway most frequently involved in signaling of TLR-mediated responses (MyD88). Studies are ongoing to describe the inflammatory components of A. fumigatus hyphae, and to define how macrophages process fungal components to trigger cytokine and chemokine release.

Antifungal Drug Resistance in Aspergillus species.

At the same time that multiple drugs have become available for treatment of invasive aspergillosis, antifungal drug resistance of Aspergillus is being recognized. However the true clinical significance of antifungal resistance remains controversial, largely due to a paucity of studies to identify and characterize resistant isolates. We identified a phenotypically and genotypically unique variant of A. fumigatus, which has a high degree of resistance to all antifungal drugs available (itraconazole, voriconazole, amphotericin B, and caspofungin). Phylogenetic studies have shown that this organism is actually a unique, cryptic species of Aspergillus, which we have proposed calling “Aspergillus lentulus”. Recent studies have identified this species among culture collections nationwide. Ongoing studies are focused on characterizing the clinical significance of this isolate, and the molecular mechanisms of drug resistance.

Epidemiologic and Clinical Studies on Fungal Disease after HSCT.

Working with a large database of clinical outcomes and patient samples, we have performed studies to define risks for infections, and to determine appropriate parameters for diagnostic tests. Prevention of infection will continue to be a theme, with current therapeutic studies addressing the utility of prophylactic antifungals in myeloablative and non-myeloablative HSCT recipients.

PUBLICATIONS

Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risks. Blood 10(13):4358-66 (2002).

Marr KA, Balajee SA, Hawn TR, Ozinsky A, Pham U, Aderem A, Akira S, Liles WC. Differential role of MyD88 in macrophage-mediated responses to opportunistic fungal pathogens. Infect Immun 71:5280-5286 (2003).

Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee A, Musher B, Corey L. Itraconazole vs. fluconazole for antifungal prophylaxis in allogeneic HSCT patients. Blood 103: 1527-33 (2004).

Balajee SA, Weaver M, Imhof A, Marr KA. Aspergillus fumigatus variant with decreased susceptibilities to multiple antifungals. Antimicrob Agents Chemother 48(4) 1197-1203 (2004).

Marr KA, BalajeeSA, LeisenringW, WeaverB, TabouretM, BentsenC and TJ Walsh.Galactomannan detection for the diagnosis of aspergillosis: Variables that affect performance. J Infect Dis 190:641-9 (2004).