Recently Tenured

Ted Hackstadt received his Ph.D. from Washington State University in 1980. He joined the Laboratory of Intracellular Parasites (LICP), NIAID, as an Expert in 1990 and is now Acting Chief of the Host-Parasite Interaction Section of the LICP.

Researchers in my lab are interested in the basic biology of bacterial obligate intracellular parasites -- in particular, Chlamydia trachomatis, one of the leading cause of sexually transmitted disease in this country and of infectious blindness worldwide.

Prokaryotic obligate intracellular parasites have evolved mechanisms that enable them to survive in extracellular environments during transit to susceptible host cells. These survival strategies generally involve a cessation of metabolic activity that can be reversed in response to environmental cues signalling arrival in an appropriate intracellular environment. Chlamydia have a complex life cycle that includes specialized cell types for extracellular survival and intracellular multiplication. During the extracellular stage of the life cycle, chlamydia take the form of small elementary bodies (EBs), with a core of condensed chromatin that disperses as the EBs differentiate into the larger, metabolically active reticulate bodies (RBs). In 1991, we found that modification of the DNA structure by histone-like proteins may be a central regulatory mechanism governing chlamydia's complex life cycle. Histone H1 homologs are rare among prokaryotes, but C. trachomatis possesses two proteins that have primary amino acid sequence homology to eukaryotic H1. These histone homologs, termed Hc1 and Hc2, are expressed only during the late stages of the chlamydial life cycle, during the reorganization of RBs into EBs, and they play a major role in establishing the nucleoid structure and controlling gene expression.

In Escherichia coli, Hc1 expression is self-limiting and produces a global termination of transcription, translation, and replication at concentrations equivalent to those found in chlamydial EBs. We have proposed that association of the chlamydial histones with DNA at levels below those causing condensation of the nucleoid may exert more specific regulatory effects through modification of DNA structure and topology, thereby influencing promoter activity and gene expression.

I am also interested in the intracellular compartmentalization of chlamydial replication. Chlamydia undergo their life cycles entirely within a vesicle that is not acidified and does not fuse with lysosomes. Lack of basic information on the physical and nutritional parameters within this vesicle, or chlamydial inclusion, severely limits attempts to identify environmental conditions that may serve to regulate the chlamydial developmental cycle. Using a variety of specific probes for various cellular organelles, in conjunction with conventional fluorescence and confocal microscopy, we have found that the Golgi apparatus may be involved in trafficking lipid to the chlamydial inclusion, implying that there is a direct interaction between the chlamydial inclusion and the Golgi network.

Christina Teng received her Ph.D from University of Texas at Austin in 1969. She came to the Laboratory of Reproductive and Developmental Toxicology (LRDT) at NIEHS in 1983 from Baylor College of Medicine in Houston. She currently heads the Gene Regulation Group in the LRDT

I began my research at NIEHS 11 years ago with a simple goal: to isolate an estrogen-responsive marker from the mouse uterus in order to study gene regulation by estrogen at the molecular level. At that time, a suitable estrogen marker for the mouse uterus did not exist. Within a year, I succeeded in purifying a 70-kDa estrogen-responsive uterine secretory protein and raised polyclonal antibody against the protein. Two years later, we cloned the cDNA of this protein and identified it as lactoferrin. Due to the diverse roles of lactoferrin in milk, neutrophils, uterus, tears, saliva, and wet-surface mucosa, nutrition, immunology, and the mammary gland have been interested in this protein for quite some time. My laboratory was the first to clone the cDNA for this biologically important protein, and published the work in 1987. Since then, our laboratory and others have isolated the lactoferrin cDNA from humans, pigs, and cows.

Lactoferrin, transferrin, and melanoma antigen p97 belong to the same gene family. Research has established that lactoferrin plays antibacterial and antiviral roles and may function in immunity, cell growth, and differentiation. Lactoferrin is differentially regulated in various tissues. Both human and mouse lactoferrin promoter-enhancer regions contain regulatory elements typical of both housekeeping and inducible genes. We found that Chicken Ovalbumin Upstream Promotor (COUP)-transcription factor competes with estrogen receptor for binding to the estrogen-response element of the lactoferrin gene in mice, but not in humans. Recently, we found a cluster of sequence elements that respond to cyclic AMP, tissue plasminogen activator, and epidermal growth factor/transforming growth factor-[[alpha]]. These results, supported by in vivo findings, suggest that the lactoferrin gene is an interesting model to use in studies of gene regulation and "cross-talk" between different signaling pathways.