ROLE OF CALCIUM-BINDING PROTEIN AND FUNCTION IN LUNG DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 other genes involved in the pathogenesis of histoplasmosis. 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 early stages of pulmonary colonization. We are also continuing studies of one of the virulence factors of Bordetella pertussis: tracheal cytotoxin (TCT) is a released fragment of peptidoglycan that is essential for triggering airway damage in whooping cough. TCT binds to a specific receptor that is a member of the peptidoglycan recognition protein (PGRP) family, and our current work is aimed at understanding host responses that include epithelial defense, cytopathology, and remodeling.