Kenneth Bayles, PhD
Professor and Vice Chairman for Research
Research Summary: Bacteria are well known for their ability to rapidly divide and reach very high cell densities in the environment or within an animal host. My research has focused on a previously undiscovered regulatory system that controls bacterial cell death. Using Staphylococcus aureus as a model system, we have demonstrated that the controlled death of bacteria is essential for normal development of multicellular bacterial communities known as biofilms. Furthermore, this research has led to the proposal that this system is functionally analogous to regulatory proteins controlling cell death in more complex organisms including humans.
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Sujata S. Chaudhari, PhD
Research Summary: Physiological significance of superoxide dismutase in Staphylococcus aureus. Reactive oxygen species like superoxide (O2•-), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•) are adventitious byproducts of aerobic metabolism that readily damage cellular macromolecules. The human pathogen Staphylococcus aureus expresses two superoxide dismutase (SOD) enzymes, SodA, and SodM, that can reduce O2•- mediated oxidative stress. Although both SODs have been shown to play important role in countering host-derived O2•-, their role in protection from endogenously produced O2•- has not yet been elucidated. In this work, we will investigate the importance of both SodA and SodM enzymes in optimal growth of S. aureus under aerobic conditions and the adverse impact of SodA and SodM mutations on S. aureus central metabolism.
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Paul D. Fey, PhD
Associate Director and Professor
Research Summary: Staphylococcus epidermidis is the preeminent cause of infections involving prosthetic heart valves, intravascular catheters, and other bio-material based devices. The most important step in the pathogenesis of S. epidermidis mediated foreign body infections is the ability of the organism to adhere and to produce biofilm on the surface of the biomaterial. After initial adherence, certain strains of S. epidermidis produce an extracellular biofilm, or polysaccharide intracellular adhesin (PIA), that is encoded by a four gene (icaA, icaD, icaB, and icaC) operon ica. We currently study the transcriptional regulation of the icaADBC operon in addition to studying the overall biofilm biology of S. epidermidis. We are very interested in arginine metabolism and its role in establishing a mature biofilm. The Fey laboratory is part of a larger group of investigators at the University of Nebraska studying the biology of staphylococci including pathogenesis, immunology, metabolism, antibiotic discovery, animal models, and biofilm.
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Stacey Gilk, PhD
Research Summary: Intracellular pathogens have clever strategies to survive inside the very cells which would otherwise kill them. The Gilk Lab studies how one bacterial pathogen, Coxiella burnetii, manipulates the host cell to form a large vacuole which supports bacterial growth. We discovered that Coxiella carefully regulates host cholesterol levels; if they do not, cholesterol accumulates in the vacuole and leads to bacterial degradation. We are investigating how Coxiella regulates cholesterol, both by directly modifying cholesterol as well as using host cell proteins to move cholesterol from one organelle to another. We are also interested in how Coxiella blocks formation of host lysosomes, which would otherwise kill the bacteria. Using a combination of cell biology, lipid biochemistry, and molecular biology approaches, this research will identify weak points in the bacteria’s strategy which can then be targeted to treat infection.
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Tammy Kielian, PhD
Research Summary: Brain abscess represents a serious infection, especially due the recent emergence of antibiotic-resistant strains of bacteria, and can cause long-term deficits including seizures and cognitive loss. Dr. Kielian’s laboratory is interested in studying how bacteria (Staphylococcus aureus) influence the immune response during brain abscess development. We utilize a mouse model of infection developed in our laboratory to study many basic questions related to how cell types native to the brain (i.e. microglia and astrocytes) and immune cells entering the infected brain from the blood recognize S. aureus through a family of molecules called Toll-like receptors (TLRs). In addition, we study how infection alters cell-cell communication in the brain that may impact the extent of tissue damage. Our research projects utilize state-of-the-art techniques such as quantitative magnetic resonance imaging (MRI) to track brain abscess evolution and exploit a comprehensive approach to infection by studying responses at the molecular and cellular levels as well as studies in the mouse model.
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Scot Ouellette, PhD
Research Summary: The Ouellette lab is interested in the consequences of reductive evolution on bacterial physiology. As Chlamydia has adapted to an intracellular niche, it has lost many genes that are present in free-living bacteria. These genes/gene pathways that have been lost through reductive evolution (Muller’s Ratchet) typically encode metabolic pathways to synthesize, for example, amino acids. Since Chlamydia relies on its host cell for many nutrients, it is not surprising that it would eliminate these types of genes. However, Chlamydia has also eliminated genes that are considered essential for viability or pathogenesis in many other bacteria. This raises many interesting questions that are the focus of Dr. Ouellette’s research as described below. Conversely, when Chlamydia has retained genes that are atypical for Gram-negative bacteria (e.g. genes normally found in Gram-positive bacteria), this is also interesting and suggests a function that is important to chlamydial growth otherwise these genes would have been deleted.
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Elizabeth A. Rucks, PhD
Research Summary: Chlamydia trachomatis is one of the most successful pathogens and is the most common cause of bacterial sexually transmitted infections. Hence, there is a great need to identify strategies to reduce/prevent transmission, limit infections to the primary site of inoculation or interrupt/control chlamydial growth and development. We are approaching this problem by studying chlamydial strategies of nutrient acquisition. Within the host cell, elementary bodies (EBs) differentiate into reticulate bodies (RBs) in a pathogen-specified parasitic organelle termed the chlamydial inclusion. To maintain its autonomy, the chlamydial inclusion interacts with very specific host cell pathways, which ultimately influences the lipid and protein content of the inclusion. Paramount to chlamydial survival within the host is the organism’s ability to obtain and utilize host cell-derived lipids. These lipids contribute to the membrane of the chlamydial inclusion, as well as, the chlamydial cell membranes. It is well established that Chlamydia will mimic the lipid composition of their host cells, but the organisms will not incorporate all available host-derived lipids into their cell membranes. The Rucks Lab focuses on the function of eukaryotic SNAREs (N-ethylmaleimide sensitive attachment protein receptor) at the chlamydial inclusion. SNARE proteins serve to decrease the energy required to fuse a host vesicle with a target membrane. In this case, the target membrane is the chlamydial inclusion. We have demonstrated that syntaxins 6 and 10 and VAMPs 3 and 4 localize to chlamydial inclusion. Further, we have demonstrated that syntaxin 6 and VAMP4 (2 out of 4 required proteins to form a fusogenic SNARE complex) interact at the chlamydial inclusion. We hypothesize that the chlamydial inclusion specifically intercepts multiple fusogenic SNARE complexes to create and maintain a defined lipid composition in the inclusion membrane. To study this hypothesis, we use proximity labeling strategies to identify membrane-protein protein interactors. We are also examining the impact of the loss of these specific SNARE proteins on chlamydial growth, development, and organismal membrane organization. We are also developing high resolution imaging techniques to try to visually capture these biochemical interactions. We are interested not only in how Chlamydia gain lipids, but why this is important to their success as a pathogen.
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Rakesh K. Singh, PhD
Research Summary: The majority of cancer deaths are a result of the cancer cells spreading from the original tumor to other sites in the body. This process is called metastasis. Our laboratory is studying some of the critical proteins that cancer cells make that help this process occur. We are also trying to define what are the important proteins that cancer cells make that enable them to go specifically to one organ rather than another. Once the important metastasis-related proteins are identified, it may be possible to block their activities as a means of treating cancer patients to prevent the spread of cancer within the body.
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Vinai Chittezham Thomas, PhD
Research Summary: My laboratory studies metabolic adaptations of staphylococci in response to various biologically relevant stresses. We have recently demonstrated that acetic acid, a byproduct of glucose catabolism, induces a novel programmed cell death (PCD) pathway in staphylococci. Although our studies have shown that acetic acid mediates its effects through intracellular acidification, the role of the acetate anion itself is unclear and an area of active research. In addition, we are currently identifying the molecular components of the PCD pathway and how PCD impacts bacterial population fitness. These projects touch upon multiple aspects of bacterial redox metabolism and physiology. Another area of active research involves understanding the physiological significance of staphylococcal nitric oxide synthase. NO is usually toxic to bacterial respiration, and it is unclear why pathogens like Staphylococcus aureus and Staphylococcus epidermidis would carry an enzyme (NOS) that makes NO. We have recently shown that endogenous NO produced by staphylococci is rapidly oxidized to nitrite and the latter species is the physiologically relevant effector of NOS function. We have determined that nitrite stimulates staphylococcal aerobic respiration and growth. How nitrite accomplishes this task is unknown and a topic that is currently being pursued in my laboratory.
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