2004 - In healthy individuals, Candida albicans, a common fungus, can multiply to become a painful annoyance, showing up as what is called thrush or oropharyngeal candidiasis (OPC). Newborns sometimes contract OPC as they pass through the birth canal, because their immune systems are not fully developed. However, the fungus also can cause another, sometimes deadly, form of disease, called hematogenously disseminated candidiasis (HDC). HDC is Candida albicans run amok throughout the body, killing 20 to 50 percent of those stricken. This systemic form of candidiasis usually requires intravenous therapy, whereas OPC is treated with topical medication.
Dr. Scott Filler, a 1999 New Investigator in Molecular Pathogenic Mycology, is keenly interested in what distinguishes OPC from HDC, and he has a hunch that different virulence factors and regulatory pathways are activated in the two types of infections. “HDC is a recent disease associated with modern medicine,” Dr. Filler says. Patients who contract HDC are typically in the hospital and have had major surgery of the gastrointestinal tract, have cancer, or have too few neutrophils—(the white cells that surround and destroy bacteria). HDC also strikes premature infants in intensive care units and individuals on broad-spectrum antibiotics. “OPC doesn’t usually progress into HDC even in immune-suppressed patients as long as their neutrophils are okay,” Dr. Filler explains.
Another compelling reason for understanding the mechanisms that drive Candida is that the pathogen, in both OPC and HDC, increasingly is becoming resistant to antifungal drugs. Because HDC can kill, the developing resistance to current treatments is alarming. Dr. Filler’s research could lead to identifying new drug targets in Candida infections or to developing vaccines to prevent the infection.
Candida is a dimorphic fungus—it can transform itself from a football-shaped yeast cell to long, many-celled filaments called hyphae. Sensors in the yeast are able to detect changes in its environment and activate a signal pathway that transforms the pathogen from yeast to hyphus—or football to filament. It is this process of transformation that most interests Dr. Filler. “If you infect mice with strains that are locked in yeast or hyphal phase, we find that they don’t get sick,” Dr. Filler notes, adding, “almost anything that blocks yeast to hyphus transition leads to reduced virulence.” So he is looking at the signals that tell cells to morph from one form to the other. Kinases—proteins that add phosphates to other molecules—often trigger this kind of change, and protein kinase A regulates the transition in Candida.
“In Candida albicans, there are two different protein kinase A catalytic subunits (parts of an enzyme complex that transfer the phosphate to molecules),” Dr. Filler explains, “one encoded by a gene called tpk1and one by tpk2. Both act on a transcription factor (a protein that binds to DNA and alters the expression of other genes) called efg1.” Do these two different subunits help tell the organism when conditions are right for a change to another form?
Dr. Filler and his colleagues set out to compare how cells lacking tpk1, tpk2, and efg1 differ in their ability to interact with oral epithelial cells, the targets in OPC, and vascular endothelial cells, the targets in HDC. In a mouse model, they were able to confirm their hypothesis that tpk1 and tpk2, as well as efg1, have different contributions to candidal virulence in thrush versus a systemic infection. In the HDC mouse model, only efg1 was required for normal virulence. But in the OPC mouse model, both efg1 and tpk2 were necessary to cause a significant infection.
“Right now,” says Dr. Filler, “we’re in the process of using microarrays to investigate the genes that are regulated by efg1 and tpk2. We’re making mutants that lack genes that are upregulated (turned on) in a virulent strain of Candida when it comes in contact with different host cells, and then we’ll test the virulence of these mutants.” Dr. Filler notes that it will be a challenge to decide which genes to examine. “Of the genes of unknown function, we’re looking for those encoding proteins that are likely to be exposed on the cell surface, because they’re more likely to be proteins that enable the organism to adhere to or invade the host cell surface. Such proteins, he says, could be targets of vaccines.
Dr. Filler’s route to infectious disease research was circuitous. A biology major at Dartmouth College, he says he went to medical school to become an orthopedic surgeon but then decided he was “better cut out to be an internist.” During his residency at Harbor UCLA Medical Center, he conducted infectious disease research with Dr. Jack Edwards, and then applied for and won an infectious diseases fellowship.
Now a professor in the Department of Medicine at Harbor-UCLA Research and Education Institute, Dr. Filler says, “I really love the mixture of research and patient care.” He is married to rheumatologist Dr. Bett Eng and is father to two daughters, two and six years old.
Dr. Filler and his wife experienced the patient side of the medical system when their now six-year-old was diagnosed with leukemia at age two. After two years of chemotherapy, his daughter is doing well, says Dr. Filler. But the going was rough in the beginning as he and his wife took turns with their daughter’s care. “I handled most of the doctor visits,” Dr. Filler says. “Because I worked mostly in the lab, my time was more flexible. What we went through with our daughter makes you see how important family is.”
Balancing work and family can be a challenge, Dr. Filler says, but he has found the equilibrium he likes between the lab and the clinic. “I probably spend 75 percent of my time doing research,” he says. “But I like doing both. Taking care of patients brings a more immediate reward and helps me focus on the important issues. Fortunately,” he adds, “I’ve had a lot of support in my institution and am not pressured to spend more time in the clinic.”
Dr. Filler credits his BWF award with jump-starting his faculty career. “As a result of my getting the BWF award, I was promoted to associate professor,” he says, adding that he also used some of his BWF award to apply for an RO1 research project grant from the National Institutes of Health and got that as well. A promotion to full professor soon followed.
Outside work and his family, Dr. Filler’s main hobby is long distance running. “I used to be an avid marathoner,” he relates, “but I’ve cut back to half marathons and now do two a year here in California.” Dr. Filler remembers his best marathon as one he ran while in college, finishing the course in 2 hours and 46 minutes. Perhaps most impressive, though, is that he finished in second place in an ultra-marathon, a punishing 41 mile test of endurance that he conquered in 5 hours and 15 minutes.