The Microbiology & Molecular Pathogenesis Program (M2P2) provides graduate students and postdoctoral fellows with first-rate training to prepare them for careers in research as competitive, independent investigators.
The program faculty's research interests span a wide range of questions regarding host-microbe interactions and related topics in microbial pathogenesis, which allows the entering trainee considerable breadth of choice of experimental systems, approaches and research topics. Our research areas include bacteria, fungi, parasites, microbe-host interactions and microbe-microbe interactions.
Brent Berwin, Ph.D.
Our interests have the theme of elucidating how leukocytes modulate host immunity, particularly in response to bacterial infection. We focus on host/pathogen interactions and, specifically, how leukocyte cell-surface receptors, including Scavenger Receptors (especially SRA) and Toll-Like Receptors, modulate the innate and adaptive immune responses of the host and how these can be harnessed to fight infection and inflammation. Recent research advances from our lab include: a genetic dissection of the comparative contribution of CD91 to calreticulin and Pseudomonas exotoxin trafficking (Walters et al., Traffic, 2005), the novel elucidation that TLR signaling controls SRA-mediated phagocytosis of bacteria (Amiel et al., Journal of Leukocyte Biology, 2009), and we have provided the first evidence showing that SRA-mediated clearance of bacterial endotoxin is functionally distinct from the role of SRA in bacterial phagocytosis and that SRA modulates the host cytokine response elicited by Pseudomonas aeruginosa (Amiel et al., Infection and Immunity, 2009). In collaboration with the O'Toole, Hogan, and Griswold labs (Dartmouth) we are continuing and extending these studies to elucidate the underlying causes and mechanisms by which bacteria colonize the lungs of Cystic Fibrosis patients and, in particular, the reasons that their innate immune responses are ineffective in the clearance and control of P. aeruginosa.
David J. Bzik, Ph.D.
Our work focuses on drug and vaccine development for treatment and prevention of Toxoplasmosis, the third most common foodborne infectious disease in the United States . Our current research efforts involve dissecting the molecular mechanisms that enable Toxoplasma gondii to steal a variety of essential resources from the host and to manipulate the host immune response to gain permanent rent-free residence in host tissues. Toxoplasma gondi has emerged as the most important current model system for studying biology of intracellular protozoan parasitism and host immune response. The research encompasses studies on drug discovery in pyrimidine and purine acquisition pathways as well as host responses affecting establishment of protective immunity and parasite persistence. These studies are generally applicable to other serious infectious diseases such as malaria, a parasitic infection that kills more than two million young children every year while also causing serious infections in 300 to 400 million adolescents and adults.
Ambrose Cheung, M.D.
Our work focuses on the regulation of virulence determinants in Staphylococcus aureus, a bacteria pathogen that has gained notoriety because of its prevalence and increasing antibiotic resistance in human infections. We employ genetic, biochemical, structural and in vivo approaches to assess the expression of virulence genes in animal models and contrasting them to laboratory conditions. We are particularly interested in virulence genes that are expressed in response to clues from stresses, host factors and those involved in cell wall synthesis and lysis. In combining these approaches, we seek to identify novel targets for the development of antimicrobial therapy.
Robert Cramer, Ph.D.
Our research group investigates the mechanisms by which the human fungal pathogen Aspergillus fumigates causes disease in immunocompromised patients. The main focus of our current studies is to understand the molecular mechanisms that Aspergillus and other human pathogenic fungi use to adapt to low oxygen microenvironments (hypoxia) that are found in vivo at sites of infection. We are also interested in how these fungal metabolic adaptations to hypoxia ultimately affect innate immune responses and infection outcomes. Thus, we are exploring the hypothesis that the interplay of oxygen homeostasis mechanisms resulting from the fungal-host interaction presents an opportunity for novel therapeutic interventions. We utilize molecular biology, genomics, biochemistry, microscopy, immunology, and animal model approaches to develop and explore our clinically relevant questions regarding these often lethal infections.
Richard Enelow, M.D.
Studies in our lab focus on immunopathogenesis of respiratory virus infection and inflammatory and immune-mediated lung disease.
Amy Gladfelter, Ph.D.
My lab is focused on how cells build large, highly organized and dynamic structures using the cytoskeleton. We focus on a conserved family of proteins, called septins. Septins are important for normal cell growth and division however intracellular pathogens co-opt the septin cytoskeleton for cell entry and motility. In our work, we combine molecular genetics, in vivo fluorescence microscopy and biochemistry to analyze the molecular organization and the regulatory pathways that direct septin assembly. We use a model filamentous fungus, Ashbya gossypii, budding yeast and mammalian tissue culture cells. Our work provides a mechanistic foundation for understanding septin organization in more complex cells such as neurons and in the unique remodeling during bacterial pathogenesis.
William R. Green, Ph.D.
Our research contributions center on obtaining a better understanding of the interplay between retroviruses and the immune system, especially killer T cells that are able to eliminate virus infected cells. We focus on defining unique viral antigens recognized by these T cells and how the virus attempts to evade the immune system. Along with investigations as to how to increase the immunogenicity of viral antigens via the innate immune system, including defining approaches towards a safer vaccination against smallpox , this research should have important implications for vaccine design and possibly immunotherapeutic approaches.
Mary Lou Guerinot, Ph.D.
One of the main goals of our research is to understand how the bacterial symbiont Bradyrhizobium japonicum interacts with its host plant soybean to regulate metabolic processes essential for the nitrogen-fixing symbiosis. Experiments underway in our lab should help elucidate how bradyrhizobia adapt to life as intracellular bacteria. Information from our studies may also be relevant to other bacteria with intracellular lifestyles, such as the animal pathogens Legionella and Brucella.
Paul M. Guyre, Ph.D
Studies in our laboratory focus on interactive mechanisms of hormone and cytokine regulation of immune function. Our goal is to better understand mechanisms that regulate macrophage and dendritic cell activation in inflammation, sepsis, autoimmunity and cardiovascular disease.
Deborah A. Hogan, Ph.D.
Deborah Hogan's research is focused on the characterization of novel virulence determinants in bacterial and fungal opportunistic pathogens. COBRE funded studies focus on a novel virulence factor regulator in the bacterium Pseudomonas aeruginosa. P. aeruginosa is an important pathogen of the lung and is associated with ventilator-associated pneumonia, chronic obstructive pulmonary disease, and chronic infections associated with cystic fibrosis (CF).
Nicholas Jacobs, Ph.D.
Emeritus Professor of Microbiology and Immunology
Jon Kull, Ph.D.
Our laboratory studies the detailed structural mechanisms employed by cytoskeletal proteins in order to 1) produce directed force along protein filaments and 2) mediate interactions with their various intra- or intermolecular protein targets. For ATP-driven molecular motors, as well as the GTP-driven G-protein family of molecular switches, conformational states are governed by the presence or absence of the nucleotide g -phosphate. An intriguing question is how such a small conformational change can be sensed by the protein and amplified, sometimes by several orders of magnitutde, in order to achieve the various cellular functions of these proteins. Our laboratory uses X-ray crystallography as its primary means of determining high resolution protein structures. In conjunction with site-directed mutagenesis, kinetics, and other biophysical techniques such as dynamic light scattering and analytical ultracentrifugation, X-ray crystallography provides one of the most powerful methods for exploring the details of protein function.
David Leib, Ph.D.
Herpes simplex virus is a common pathogen which causes a variety of diseases ranging from common cold sores and genital sores, to sight-threatening herpes stromal keratitis and life-threatening encephalitis. HSV exhibits two different modes of gene expression during its life cycle. During the acute phase of infection all of its genes are expressed, yet during latency viral gene expression is almost completely repressed. This unusual lifecycle allows HSV to persist for the lifetime of the host. HSV encodes many genes that serve to modulate the host immune response. The major goal of our research is to elucidate the mechanisms by which HSV manages to evade both the innate and adaptive immune responses. Our approach is to generate recombinant viruses and use them in vitro and in vivo to study the impact of specific viral genes on immune evasion and pathogenesis. Our work impacts on vaccine development and identification of novel targets for antiviral drug discovery.
Dean Madden, Ph.D.
The goal of research in the Madden lab is to understand the functional characteristics of ion channels in terms of their molecular structure and interactions. Dean's group investigates the regulation of ion channel activity through interactions with PDZ proteins that guide intracellular trafficking, uptake, and recycling. Our particular focus is on CFTR, the chloride channel mutated in patients with cystic fibrosis. We use biophysical techniques to study both endogenous (human) and exogenous (bacterial) proteins that destabilize CFTR, leading to a breakdown of antibacterial defenses in the lung. In addition, we use electron microscopy and X-ray crystallography to study conformational changes in glutamate receptor ion channels that are responsible for triggering and controlling post-synaptic neuronal signals.
Jason McLellan, Ph.D.
We are interested in elucidating the molecular mechanisms of these host-pathogen interactions, particularly those involving viral glycoproteins. Our ultimate goal is to translate the structural and mechanistic information that we obtain into the development of vaccine antigens, prophylactic or therapeutic antibodies, and small molecule inhibitors.
Larry Myers, Ph.D.
Our research is focused on discovering how epigenetic transcriptional states are established and maintained in S. cerevisiae and pathogenic fungi. An epigenetic change in gene expression is an alteration in the state of expression of a gene that does not involve a mutation, but that is nevertheless inherited in the absence of the signal (or event) that initiated the change. There are many examples of epigenetic regulation from bacteria to mammals. We are particularly interested in epigenetic phenotypic switching mechanisms in pathogenic fungi that are critical for their infectivity in immunocompromised patients in the clinic. In eukaryotic cells, many epigenetic transcriptional states are associated with changes in the structure and post-translational modification of chromatin. The two major questions in this field are: How are epigenetic transcriptional states inherited? and once established how do these states confer a state of expression or silencing on particular genes? Our current research is focused on two unexpected discoveries we have recently made regarding the mechanisms of epigenetic transcriptional silencing. The first discovery revealed a role for chromatin interactions and post-translational modification of histones in the regulation of a co-activator complex previously thought to function through non-chromatin based mechanisms. The second discovery involves the biochemical characterization of a epigenetic master regulator of phenotypic switching in C. albicans that suggested the protein uses a prion-like mechanism in its function. We are investigating these phenomena in both S. cerevisiae and pathogenic fungi.
Randolph J. Noelle, Ph.D.
In 1991, my laboratory identified a novel membrane protein expressed on helper T lymphocytes (Th), CD154. The receptor for CD154 is CD40. CD40 is expressed on B lymphocytes and antigen-presenting cells. This ligand-receptor pair plays a central role in the control of antibody- and cell-mediated immunity. Intervention in CD154-CD40 interactions (by genetic deletion or antibody-blockade) can block a wide spectrum of immune and autoimmune responses as well as transplantation rejection. As a result, the laboratory has focused on four areas of immunobiology that are relevant to CD40 function.
CD40 signaling. For the past 6 years we have been actively involved in trying to unravel the biochemical signaling cascade that transpire as a consequence of CD40 signaling. We have produced a set of Tg mice that have defined mutations in the cytoplasmic domain of CD40.
Inflammation in the CNS. Since early in the CD154 story, we have been involved in deciphering its role in inflammation. Studies have clearly shown that one can readily prevent disease development, as well as intervene in disease progression. Our efforts now and into the future are to understand the relationship between the peripheral immune system and the immune system within the CNS in controlling T cell recruitment, tolerance and inflammation.
B cell memory and plasma cell development. Our goals are to understand the factors that control the remarkable longevity of plasma cells and memory B cells in mice. Studies using global gene analysis have and will lead to novel genetic targets that allow us to understand the mechanisms that allow the persistence of these cells in humans for decades.
Immune tolerance in transplantation. Perhaps the most impressive activity of ±CD154 is its ability to block the rejection of fully allogeneic skin, heart, kidney and islet allografts in mice, and in some of these cases in monkeys. Exciting new insights into how ±CD154 induces peripheral T cell tolerance and long-lived graft acceptance have emerged from these studies. The impact of ±CD154 on T cell anergy, regulatory T cell function, and dendritic cell biology are all elements in engendering permanent allograft survival.
George A. O'Toole, Ph.D.
Our work focuses on the formation of surface-attached microbial communities known as biofilms. Once these microbial communities form they are highly resistant to antibiotics. The formation of biofilms of organisms such as Staphylococcus aureus and Pseudomonas aeruginosa on a variety of medical implants (such as catheters, contact lenses and artificial joints) and their resistance to treatment by standard antibiotic therapy represents an important clinical problem that costs the healthcare system over $1 billion dollars annually. We are also interested in the role of biofilms in microbial pathogenesis.
Elmer Pfefferkorn, Ph.D.
Emeritus Professor of Microbiology and Immunology
C. Fordham von Reyn, M.D.
Dr. von Reyn's research focus is HIV-associated tuberculosis in the developing world. He is PI for an NIH-funded Phase III trial of a new TB vaccine for HIV positives based in Tanzania and PI for a Fogarty AIDS International Training and Research Program between the Geisel School of Medicine at Dartmouth and the Muhmibili University College of Health Sciences in Dar es Salaam , Tanzania .
Charles Sentman, Ph.D.
This laboratory investigates the function of NK cells and cell receptors in response to infection and tumors. NK cells are part of the innate immune response and have the ability to recognize tumor cells and some virus infected cells. Early activation of NK cells may result in the induction of specific adaptive immune responses that are important for host protection. We are investigating the mechanisms for recruitment and activation of NK cells to tumor cells and endometrium. We study both human and murine NK cells.
Karen Skorupski, Ph.D.
Our research focuses on understanding the complex mechanisms utilized by pathogenic bacteria to regulate virulence gene expression in response to environmental stimuli so that better strategies can be developed to control and prevent bacterial infections.
Elizabeth Smith, Ph.D.
Cilia and flagella are found on diverse cell types including sperm cells of vertebrates and some invertebrates, unicellular protozoa, and several vertebrate epithelial cell types. In mammals, for example, motile cilia found on epithelial cells lining the brain ventricles circulate cerebrospinal fluid; oviduct cilia move the fertilized egg to the uterus; and cilia in the respiratory tract sweep debris from the lungs. Because of the diversity of cell types that utilize these organelles for specific functions, individuals with primary ciliary dyskinesia may present with a variety of symptoms including impaired fertility and chronic respiratory infections. Regardless of the cell type, the motility of all eukaryotic cilia is tightly regulated. For example, the motility of cilia associated with respiratory epithelial cells is modulated to increase mucociliary clearance in response to pathogen infection. We are interested in understanding the complex regulatory cues that modulate ciliary beating. This regulation is mediated in part by a signal transduction pathway that includes second messengers, as well as kinases and phosphatases anchored to the axoneme. Our goal is to understand how these signal transduction pathways are integrated to produce the complex waveforms typical of beating cilia.
Bruce A. Stanton, Ph.D.
There are four major research programs in the Stanton laboratory: (1) "Integrative genomics and proteomics of cystic fibrosis". The goal of this project is to utilize genomic and proteomic approaches to elucidate the CFTR interactome and to elucidate the cellular and molecular mechanisms whereby these interacting proteins regulate CFTR function and trafficking; (2) "Host-pathogen interactions in Cystic Fibrosis". The goal of this project is to elucidate how Pseudomonas aeruginosa infects airway epithelial cells and forms drug resistant biofilms in patients with CF, and to understand how airway epithelial cells facilitate drug resistant by Pseudomonas aeruginosa using genomic and proteomic approaches; (3) "CF drug discovery". In collaboration with several biotechnology companies the Stanton laboratory is developing new therapeutics approaches to treat and cure CF and (4) "Arsenic and the ubiquitin - lysosomal pathway". The goal of this project is to elucidate how very low levels of environmental toxicants, primarily arsenic, affect lung function and human health using genomic, proteomic and physiological approaches to elucidate the cellular mechanisms whereby arsenic adversely affects physiological systems, and to assess the relevance of these observations to human health.
Paula Sundstrom, Ph.D.
We are discovering fungal specific targets and drugs for treatment and prevention of vaginitis, oral thrush and invasive human diseases caused by the yeast germ Candida albicans . Currently we are focusing on neutralizing the function of a fungal surface protein which forms tight attachments to vulnerable sites on human stratified squamous epithelium. The drugs will be useful for preventing yeast infections in infants, transplant patients, those with malignancies, with HIV infection, with diabetes and numerous others at risk for candidiasis.
Surachai Supattapone, M.D., Ph.D., D.Phil.
Our laboratory works on the pathogenesis of prion diseases such as scrapie and chronic wasting disease. These unusual infectious diseases appear to be caused by a misfolded protein called PrP, and we are studying how PrP misfolding occurs, and kills cells of the brain.
Ronald K. Taylor, Ph.D.
The Taylor laboratory studies the intestinal pathogen Vibrio cholerae, specifically the regulation of bacterial virulence gene expression in response to encountering a suitable host environment and the molecular mechanisms that mediate intestinal colonization. They collaborate with the Kull lab to study the biophysical properties of transcription factors active in this process. The Taylor lab is elucidating the mechanisms of host colonization, extracellular protein secretion, and is identifying new bacterial virulence determinants. They are developing new tools to facilitate genetic analysis of bacterial pathogens, design vaccines, and to characterize novel antibiotic targets, as well as developing small molecule inhibitors of the key mechanisms of pathogenesis that they discover.
Edward Usherwood, Ph.D.
The goal of my laboratory is to have a better understanding of the relationship between the immune reponse and chronic virus infections. We study gammaherpesviruses, which can give rise to tumors in the immunosuppressed and AIDS patients. This knowledge will lead to better vaccines and immunotherpies to combat this important class of persistent virus infections.
Charles R, Wira, Ph.D.
Michael E. Zegans, M.D.
Professor of Surgery (Ophthalmology) and of Microbiology and Immunology
- Clinical: Diseases of the cornea, ocular surface and uveitis.
- Surgical: Corneal transplantation, cataract surgery, conjunctival tumors .
- Research: Ocular microbiology and bacterial biofilm formation.
Research-track faculty and emeritus faculty do not accept Ph.D. students.