May 1, 2001

NIDCR Announces Funding of New Grants on Oropharyngeal Candidiasis

To accelerate research on the causes and treatment of oropharyngeal candidiasis (OPC)--the oral yeast infection more commonly known as thrush--the NIDCR has announced the funding of seven new grants. The projects, totaling $2 million, will explore host immunity to this infection with the aim of developing new treatment strategies for OPC, which is rapidly becoming drug resistant.

Oropharyngeal candidiasis (OPC) occurs when there is an overgrowth of Candida, a fungus that most people harbor in low numbers on the mucus membranes of their mouth and throat. Because the immunologic processes that keep oropharyngeal candidiasis in check in the body are not known, NIDCR is funding projects that will examine this important yet understudied area of research. Knowledge of the underlying mechanisms of host defense to Candida and the genes that can be turned on to prevent overgrowth should lead to better prevention and treatment, including the development of safe and effective vaccines.

"The NIDCR has supported research on Candida for many years," explained Dr. Lawrence Tabak, Director of the NIDCR. "Because of the prevalence of Candida in AIDS patients, infants, and people receiving immunosuppressive therapy for diseases such as cancer, it is important to do this type of research. With advances in our understanding of the immune response to this infection, we have new opportunities to develop innovative treatment approaches."

OPC causes unsightly, white patches in the mouth that may be painful and may make chewing and swallowing difficult. HIV-infected individuals and those with AIDS are at greatest risk of developing oropharyngeal candidiasis, as are newborns, diabetics, smokers, denture-wearers, and patients receiving antibiotics or chemotherapy. Because OPC is a harbinger of acute HIV infection, the presence of these telltale white patches in the mouth may provide an easy way for dentists and physicians to screen for HIV. OPC is the most common HIV-associated disease, and its occurrence often serves as a predictor of immunodeficiency. It also can predict immunodeficiency in patients with debilitated immune systems due to other disease processes.

Of particular concern to the medical and dental community is that OPC is becoming drug resistant. While the condition is commonly treated with topical or systemic antifungal agents that may make the symptoms better, these drugs do not necessarily eradicate Candida colonization, and recurrence is common. Recent reports indicate that certain azole drugs such as Diflucan used to contain recurrent cases of OPC are no longer effective, indicating that some Candida organisms may be developing drug resistance.

The seven NIDCR-supported projects cover a wide array of approaches to understanding host response to Candida infection. At Columbia University in New York, Dr. Anna Dongari-Bagtzoglou is focusing on neutrophils, white blood cells that combat infection and protect the host from Candida infection. Evidence suggests that when oral epithelial cells interact with Candida, they release specific cytokines, or peptides, that have biological effects on neutrophils. Neutrophils then accumulate rapidly at the site of infection in the oral cavity and help in the local control of Candida growth and invasion. Dr. Dongari-Bagtzoglou is looking at the host signals that trigger these events to learn what directs the neutrophils and causes them to turn on.

At the UCLA School of Medicine, Dr. Scott G. Filler is studying the molecular events associated with host invasion. His goal is to identify the signals that cause C. albicans to spread out long filaments in its search for nutrients, a process that is critical to how the infection spreads. This ability of C. albicans to change its shape and produce long filamentous forms is dependent upon intracellular signals. These same signals also cause the cell to secrete virulence factors that enable the organism to adhere to and invade oral tissue, and ultimately cause tissue destruction. Dr. Filler is concentrating on these virulence factors as potential vaccine targets.

Using a synthetic approach, Dr. Robert J. Woods at the University of Georgia is focusing on the development of an effective anti-Candida vaccine. He has determined that certain peptides found on the surface of Candida organisms elicit immune responses in mice that confer protection against OPC. Enhancement of the immunogenicity of these peptides may lead to the development of a powerful vaccine.

At the University of Wisconsin Medical School, Dr. Edward Balish is working with a mouse model that mimics the OPC seen in dental and AIDS patents. He is looking at specific T cells (lymphocytes) and neutrophils to see what role they play in protection against OPC. Identification and better understanding of their involvement in resistance to infection may be critical to the development of effective immunotherapy for OPC.

Dr. Soon-Cheol Hong at the Medical College of Ohio is examining how host immune cells (macrophages) recognize C. albicans. Increased knowledge of the interaction between pathogenic yeasts and specific cell receptors on the surfaces of macrophages should lay a foundation for the development of immunological strategies that will augment defense responses in OPC and other infectious diseases.

Focusing on the innate immune system, Dr. Aaron Weinberg at Case Western Reserve University is studying antifungal peptides known as human beta defensins 1 and 2, which are secreted by mucosal epithelial cells. These peptides may be a first line of defense against microbial pathogenesis. While some strains of Candida stimulate production of beta-defensins, others do not. Dr. Weinberg is exploring which Candida strains stimulate beta-defensins, with the goal of increasing peptide production. In light of the frequent use of antibiotics and antimycotics in treating oral diseases and the threat of microbial resistance, investigations into novel peptides such as beta-defensins may offer future clinical promise.

At the University of Florida, Dr. Minh-Hong T. Nguyen is exploring virulence factors that are turned on exclusively when Candida is growing in the body. Using a sophisticated system called In Vivo Induced Antigen Technology (IVIAT), the investigator will identify antigens expressed by C. albicans during OPC infection that likely are important virulence factors. This study should provide insight into the mechanisms by which C. albicans is transformed from a harmless, commensal organism into an invasive pathogen. Identification of the virulence factors will increase understanding of the host response to OPC and lead to potential applications for drug, vaccine, or diagnostic test development.