William Goldman, PhD

Professor and Chair, Microbiology and Immunology, School of Medicine

Goldman


Email: wgoldman@email.unc.edu









Education

B.S.,Indiana University,1976
Ph.D., University of North Carolina, Chapel Hill, 1980

Research Interests

Pathogenesis of bacterial and fungal infections of the respiratory tract: histoplasmosis, pneumonic plague, and pertussis.

Research Summary

 

Successful respiratory pathogens must be able to respond swiftly to a wide array of sophisticated defense mechanisms in the mammalian lung. In histoplasmosis, macrophages — a first line of defense in the lower respiratory tract — are effectively parasitized by Histoplasma capsulatum. This process depends on virulence factors produced as this "dimorphic" fungus undergoes a temperature-triggered conversion from a saprophytic mold form to a parasitic yeast form. One such molecule is a calcium-binding protein (CBP) that is secreted preferentially by the yeast form and is essential for Histoplasma virulence. The experiments to unravel CBP structure and function have relied heavily on our development of a telomeric shuttle plasmid that has been used for complementation cloning, gene disruptions, RNA interference, and reporter gene constructs. In addition, random insertional mutagenesis and transcriptional profiling with microarrays are helping us identify and characterize genes involved in the regulation of CBP1 expression.
Another yeast phase-specific product of H. capsulatum is alpha-(1,3)-glucan, a cell wall polysaccharide that is associated with virulence in a variety of fungal pathogens. We have taken two approaches to study alpha-(1,3)-glucan: the first is a forward genetics strategy, using Agrobacterium-mediated insertional mutagenesis, to identify genes implicated in the regulation, synthesis, and processing of this polysaccharide. The second approach uses reverse genetics, combining fungal gene disruption with mammalian RNA-interference, to study the genes involved in production of and response to alpha-(1,3)-glucan. This work has revealed that alpha-(1,3)-glucan on the surface of Histoplasma yeasts masks recognition of the underlying beta-glucan by dectin-1, a macrophage pattern-recognition receptor that is critical in the innate immune response to fungi.
Yersinia pestis also displays two temperature-regulated lifestyles, depending on whether it is colonizing a flea or mammalian host. Inhalation by humans leads to a rapid and overwhelming disease, and we are trying to understand the development of pneumonic plague by studying genes that are activated during the stages of pulmonary colonization. We have developed and characterized a mouse model for studying the pathological and immunological changes during the progression of pneumonic plague. This model system has revealed two sharply contrasting phases to the syndrome: the first phase of infection features rapid bacterial proliferation in the lung, but almost no inflammatory response, symptoms, or pathology; the second phase, starting at approximately 36 hours post-inoculation, is marked by inflammation and pneumonia that lead quickly to death. The utility of this model was highlighted in a study that demonstrated how a plasminogen-activating protease (encoded by the pla gene of Y. pestis) is essential for development of the second phase of this disease. Most of our current work is focused on understanding the bacterial and host mechanisms responsible for controlling these two phases of pneumonic plague.
We are also continuing studies of one of the virulence factors of Bordetella pertussis: tracheal cytotoxin (TCT) is a released fragment of peptidoglycan that causes pulmonary inflammation in pertussis (whooping cough). TCT and endotoxin synergistically trigger respiratory epithelial production of nitric oxide, causing ciliated cell damage that corresponds to the well-known airway cytopathology of pertussis. A variety of host receptor systems have been shown to recognize peptidoglycan fragments, and some – such as the PGRP family – are evolutionarily conserved from flies to mammals. Depending on the relationship between bacteria and host, the results of exposure to TCT can be beneficial or pathological. Our current work is aimed at understanding host responses to TCT that include epithelial defense, cytopathology, and remodeling.

 

Publications

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Goldman Biosketch