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Bioinformatics Analysis Leads to New Understanding of Infectious Yeast

People with compromised immune systems—such as those suffering from AIDS or organ transplant recipients—face innumerable challenges from possible sources of infection. Among their concerns is a yeast, Cryptococcus neoformans, that can cause inflammation in the nervous system and brain. In the developing countries of Asia and Africa, C. neoformans infection, or cryptococcosis, accounts for an estimated 17 percent of AIDS-related deaths. Worldwide, more than 600,000 deaths each year result from the disease.

Petri dish showing infection with Cryptococcus neoformans
Infection with Cryptococcus neoformans, shown here, accounts for more than 600,000 deaths worldwide each year.
Credit: CDC

Searching for Clues

How does C. neoformans gain access to the immune system? What makes it so virulent? Does the yeast have any weak points that can be attacked? These are the questions that Peter Williamson, M.D., Ph.D., seeks to answer. He is an investigator in the NIAID Laboratory of Clinical Infectious Diseases and chief of its Translational Mycology Unit.

Dr. Williamson sought to characterize a novel protein, called Sp1, in C. neoformans and understand its role in the yeast’s virulence. He first thought that, similar to proteins in other yeasts, Sp1 needed calcineurin—an enzyme involved in the growth and differentiation of certain immune cells—to activate. However, Dr. Williamson and his colleagues found no evidence that Sp1 needed calcineurin, so they continued their search.

Analyzing Sp1 Evolution With Bioinformatics

Dr. Williamson and his team turned to NIAID bioinformatics experts, who support investigations by helping predict, characterize, and analyze the structural, functional, and evolutionary aspects of genes and proteins involved in the survival or spread of disease-causing organisms.

A screening system using microarray analysis allowed Dr. Williamson’s team to compare Sp1's gene-expression, or transcriptional, profile to the profiles of other, more well-known protein mutations. Using this screen, they characterized Sp1 as belonging to the protein kinase C (PKC1) pathway, a major cellular pathway that mediates the way C. neoformans reacts to environmental stressors like changes in temperature, pH, and nutrients. This finding showed that Cryptococcus Sp1 is more similar to human Sp1 than it is to other yeast proteins, demonstrating an evolutionary shift in Sp1 that has helped shape its role in disease. NIAID's bioinformatics team then performed an analysis of Sp1’s gene sequence and compared it to similar proteins; their data analysis corroborated the results of the screening system.

Knowing that Sp1 belongs to the PKC1 pathway enables researchers to find new ways to block the protein’s function. A drug that interferes with Sp1 activation could potentially treat or prevent cryptococcosis and make a tremendous impact on global health. Dr. Williamson and his team will continue to work with the bioinformatics team at NIAID to identify novel targets of the PKC1 pathway, creating models of these proteins to better understand how their role in cryptococcosis.

Dr. Williamson’s Lab

Last Updated May 17, 2012

Last Reviewed May 17, 2012