Research Interests

We are all kept alive by the activities of our immune systems in protecting us from infection by the earth’s microbes. Think of the ending in the movie War of the Worlds. Nowhere is the made more obvious than by our relationship to a ubiquitous filamentous fungus named Aspergillus fumigatus. This fungus grows in the soil where it degrades dead plant material as its food source and produces abundant airborne spores for its reproduction and dispersal. All of us breathe in these spores on a daily basis where they are killed by cells in our lungs call alveolar macrophage. These cells are participants in our innate immune system. Those few spores that manage to not be killed by our macrophages and germinate to form filaments are killed by another innate immune cell recruited to the lungs. These cells are the neutrophils and they are recruited from our blood. Some modern therapies for cancer and other disease use solid organ or bone marrow transplants or involve the administration of toxic chemotherapeutic agents. These therapies cause the destruction of neutrophils or include the suppression of the immune system to prevent transplant rejection. These treatments particularly disable the macrophage and neutrophils. These therapies put patients at particular risk for a disease call invasive aspergillosis. The disease occurs when the patient inhales A. fumigatus spores that are no longer killed by the disabled macrophage and neutrophils. The resulting fungal filaments invade the lung tissue and are transported by the circulatory system where they can infect any tissue of the body. Invasive aspergillosis has a mortality of 50 to 90% because diagnosis is difficult and typically late, after the disease is well advanced, and because the antifungal drugs used to treat the disease are not very effective.

The focus of the invasive aspergillosis research in our group is on the details of the interaction between the fungus and the mammalian host. Understanding the details of this complex interaction in an immune suppressed host will potentially reveal approaches to managing this terrible disease. Because it is a disease that is clearly the result of the details of the interaction between the host and the fungus, therapeutic or preventive approaches may emerge from the perspective of killing or disabling the fungus from augmenting or otherwise strengthening the patient’s immune system or perhaps a combination of both.

Our group at JCVI is studying a horse pathogenic bacterium Burkholderia mallei which causes a severe disease called glanders and a very closely related pathogenic soil organism called Burkholderia pseudomallei. B. pseudomallei causes a disease very similar in symptoms to glanders called melioidosis. Melioidosis is a public health issue in the tropical areas of Northern Australia and South East Asia where B. pseudomallei lives in the wet soils. Both organisms are classified as select agents by CDC because of their potential for use as weapons. The research focuses on a process call quorum sensing. This process allows for cell to cell communication in populations of these bacteria and controls virulence as well as other population processes such as the formation of biofilms. The goal of the research is to characterize the genes regulated by quorum sensing and explore how disrupting this quorum sensing control process might be used as a way to help manage infections.

Selected Publications

• Fedorova, N.D., Harris, S., Chen, D., Denning, D., Cotty, P.J., Nierman, W.C. Using aCGH to study intraspecific genetic variability in two pathogenic molds, Aspergillus fumigatus and Aspergillus flavus., A. fumigatus and A. flavus. Medical Mycology, 17:1-8. PMID 19291596, 2009.
• Duerkop, B.A., Varga, J., Chandler, J., Peterson, S.B., Herman, J.P., Churchill, M.E.A., Parsek, M.R., Nierman, W.C., Greenberg, E.P. 2009. Quorum-sensing control of antibiotic synthesis in Burkholderia thailandensis. J. Bacteriol., In press, 2009.
• McDonagh A., Fedorova N.D., Crabtree J., Yu Y., Kim, S., Chen, D., Loss, O., Cairns, T., Goldman, G., Armstrong-James, D., Haynes, K., Haas, H., Schrettl, M., May, G., Nierman, W.C., Bignell, E. Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLoS Pathog. 4:e1000154.PMID 18787699, 2008.
• Sugui, J.A., Stanley, S.H., Zarember, K.A., Chang, Y.C., Gallin, J.I., Nierman, W.C. and Kwon-Chung, K. J. 2008 Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils, PLoS ONE, 3:e2655. PMID: 18648542, 2008.
• Nierman, W.C., Pain, A., Anderson, M.J., Wortman, J., Kim, H.S., et al. Genomic sequence of the pathogenic and allergenic filamentous fungus, Aspergillus fumigatus. Nature 438:1151-1156, 2005.
• Nierman, W.C., D. DeShazer, H. Kim, H. Tettelin, K. E. Nelson, et al. 2004. Structural flexibility in the Burkholderia mallei Genome. Proc. Natl Acad. Sci. USA. 101: 14246 – 14251, 2004.