By David N. Leff
Can a fungus whose Latin name means ¿dazzling white¿ ¿ and which causes a disease with the melodious moniker ¿thrush¿ ¿ be all bad?
The answer is yes. Fungal molecular biologist Paula Sundstrom opined, ¿If we eradicated Candida albicans from the face of the earth, I don¿t think anyone would suffer.¿
Millions of people do suffer from Candida¿s infectious depredations, which range from mild to fatal. Its earliest and best-known form is oral candidiasis, or ¿thrush¿ (the word goes back to Old Norwegian). This is a spread of creamy white patches, which can be scraped off the painfully inflamed inner cheeks and tongues of infants, especially preemies.
Sundstrom, an associate professor of medical microbiology and immunology at Ohio State University, in Columbus, presented a research paper on Candida last Monday morning to a special meeting of the American Society for Microbiology, in Charleston, S.C. She told the session on ¿Human Host Cell Recognition and Invasion¿ of her team¿s recent discovery of the piratical mechanism by which the fungus grapples to human mucosal and epithelial cells.
An almost identical version of her presentation appears in today¿s issue of Science, dated Mar. 5, 1999, and is titled ¿Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1 [protein].¿
¿A clinician in the audience,¿ Sundstrom told BioWorld Today, ¿said that infants who are born prematurely may get serious Candida infections, because their immune system hasn¿t developed, and that there can be nervous-system sequellae. The organism also causes vaginitis in women, which was discussed here at the meeting. We need more methods of diagnosis and treatment.¿
Candida albicans colonizes the gastrointestinal tract of virtually every human being on earth, Sundstrom pointed out. ¿If you take about half the population and culture their saliva,¿ she said, ¿you¿ll get colonies of the organism. Most of us have no problems. It¿s just the normal oral and intestinal flora. But it¿s an opportunistic pathogen, and when the conditions are right, candidiasis can make real trouble.¿ Among these serious to fatal systemic complications of Candida infection are endocarditis, septicemia and meningitis. In hospitalized patients, this fungus ranks among the top five pathogens.
Fungal Protein Pirates Host Enzyme
¿The main thing about the Science paper,¿ Sundstrom told BioWorld Today, ¿is our discovery of this adherence-promoting Hwp1 protein ¿ Hwp stands for Hyphae wall protein¿ ¿ and our showing that it is the substrate, or binding agent, for the human host enzyme, transglutaminase (TGase). It¿s present in cells on our oral mucosal surfaces.
¿The Hwp1 protein,¿ she continued, ¿is made on the surfaces of Candida albicans germ tubes, or hyphae. These are filamentous growth structures that the fungus produces for binding to its host¿s cells. We found the protein to be a substrate for that mammalian TGase, which is a most unusual enzyme. The reason it¿s present in the host is to cross-link different proteins at the cell surface, to form a very stable innate barrier defense on our mucous surfaces. It also works in the skin, and has implications for microbial diseases other than candidiasis.
¿That¿s its function in the human host,¿ Sundstrom said, ¿but some of this enzyme activity is expressed and available outside the cells, and apparently that fungal protein takes advantage, or pirates, the use of that host enzyme to allow it to attach and form a colony there on the mucosal surfaces. That helps it to grow in the host, and produce more and more numbers of organisms that can ultimately lead to problems for patients.¿
Mice Demonstrate Protein¿s Function
Sundstrom disrupted the Hwp1 protein¿s gene in the fungal genome, and made knockout strains of Candida that can¿t express this protein. ¿And we made other strains¿ she said, ¿where we put the gene back. We could show that only the strains that had the protein encoded by this gene were able to covalently attach to our host cells.¿
To confirm this in vitro finding in vivo, ¿we injected our different strains ¿ with or without this protein ¿ into mice. We wanted to see if the presence of Hwp1 was important in one model of the disease. The mice that got the strain that didn¿t make that important protein substrate did not all die at the 30-day endpoint. Only one mouse in six died. In the other group, which got the strain of Candida that had the gene encoding this Hwp1 protein, out of 18 mice, only two were left alive on the 30th day.¿
She added: ¿This is just one kind of data that we hope to follow up in future studies on the importance of this protein in disease. We hope to find ways to inhibit this stable interaction. And we have some ideas about how we¿re going to approach this. We think that if we can inhibit this interaction in individuals who are at risk for candidiasis ¿ those who are immunosuppressed ¿ then we can find a nontoxic inhibitor of this interaction that will prevent Candida from being able to make stable attachment and cause infection. And that¿s what we want to do, to prevent candidiasis.¿
Sundstrom is inventor of a patent application she has filed to protect the development of strategies for inhibiting this kind of adhesion.
¿I think the main thrust of our research,¿ she observed ¿ one of the main reasons it got into Science ¿ is that this mechanism of covalent adhesion between microorganism and host has not been described for any other microorganism ¿ not bacteria, not viruses, not parasites, or any other fungi. So, it¿s a very novel interaction to have a fungal protein being a substrate for a mammalian enzyme.¿
The advent of AIDS offered C. albicans a new target of opportunity, Sundstrom pointed out.
¿The incidence of candidiasis has greatly increased in recent years, and AIDS was part of that,¿ she said. ¿But also, as we develop better methods to prolong life ¿ of life support, in terms of organ transplantation procedures; [and] in terms of treatments for malignant diseases, as there are more patients able to survive longer because of better medical care ¿ that creates a growing subgroup at higher risk of candidiasis. It¿s really emerging in importance, because of the human host population, not because Candida is becoming a more virulent organism. It¿s just doing what it¿s always done.¿ n