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.
James Bliska, Ph.D.
My long-term research focus is to understand how bacterial toxins interact with the immune system to trigger pathogenesis or host protection. At Dartmouth, I will expand my research to investigate opportunistic bacterial pathogens that produce toxins and cause mucosal infections, such as those that occur in the lungs of Cystic Fibrosis patients. I will also be using "synthetic immunology" to develop novel therapeutics to combat opportunistic mucosal pathogens.
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.
Karl Griswold, Ph.D.
Enzymes have the potential to revolutionize a huge array of technical fields including but not limited to chemical synthesis, biofuel production, waste remediation, and treatment of human disease. Unfortunately, evolution of enzymes in their natural context frequently places constraints and limitations on their functionality in environments typical of practical applications. The Griswold research laboratory seeks to circumvent these limitations by developing and applying protein engineering techniques to redesign nature's biocatalysts at the molecular level. Our objective is to generate novel biomolecules that exhibit superior activity relative to their natural counterparts.
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.
Annie G. Hoen, Ph.D
Dr. Hoen's research aims to develop new approaches to understanding the complex interactions between human health, commensal and pathogenic microorganisms, and the environmental determinants of disease risk. Her current research is focused on the establishment of the human microbiome in infancy in light of common early life exposures and health outcomes in childhood. Specific projects include studies of network-based methods to capture the evolving interactions between the microorganisms that form the intestinal microbiome in infants and young children; the environmental drivers of infant intestinal microbiome development; associations between patterns of infant intestinal microbiome establishment and health outcomes in children; and the role of the intestinal and airway microbiomes in the clinical progression of cystic fibrosis. Other research interests include identifying the determinants of infectious disease risk, emergence, temporal dynamics and geographic spread and the application of microbial genomics to infectious disease outbreak investigation.
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.
Wil Leavitt, Ph.D.
Microbes are central players in Earths' elemental cycles. Microbial cells, enzymes and reactive intermediates drive the biogeochemical cycles on our planet by supporting the establishment and persistence of complex chemical reaction networks and ecosystems. The research in my group centers on experiments designed to reveal the fundamental microbiological and environmental (physicochemical) controls on microbial geochemistry that drive the biogeochemical cycles of Earth. Using observations from stable isotope geochemistry, biochemistry and microbial physiology we work to constrain energy fluxes and transformation rates within the elemental cycles (C, S, O, N, P and H) as well as intimately linked metal cycles (e.g. Fe, Mn, and more). To address these challenges we utilize state-of-the art tools — including in vitro enzymology, stable isotope and organic geochemistry, in parallel with the cultivation and manipulation of anaerobic microbes in chemostats of our own design.
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.
Lee Lynd, Ph.D.
A central theme of the Lynd group is processing cellulosic biomass in a single step without added enzymes. Such "consolidated bioprocessing" (CBP) is a potential breakthrough, and "is widely considered to be the ultimate low-cost configuration for cellulose hydrolysis and fermentation" (joint DOE/USDA Roadmap, 2007). We are focused on production of ethanol, a promising renewable fuel. The CBP strategy is however potentially applicable to a very broad range of fuels and chemicals.
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.
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.
Carey Nadell, Ph.D.
Bacteria often live in groups, called biofilms, where they cooperate and compete using a broad spectrum of interactive behaviors. These interactions are central to how bacteria evolve, and how they cause disease. We use molecular genetics, confocal microscopy, computational simulations, and evolutionary analysis to understand the mechanisms and biofilm-scale consequences of bacterial cell-cell interaction.
Randy Noelle, Ph.D.
Our laboratory has been involved with numerous translational efforts in the areas of antibody-based immunotherapy and cellular vaccines for cancer. We have produced monoclonal antibodies that have entered clinical trials at Dartmouth and around the world, and we have played an active role in the development of clinical trials for cellular vaccines for cancer. We continue to aggressively translate basic scientific discoveries into the clinic and measure the impact of these interventions using highly sophisticated measurements of human immunity.
Joshua Obar, Ph.D.
Our laboratory is currently using gene knockout mice, adoptive cell transfer, bone marrow chimeras, and therapeutic administration of cytokines and chemokines to explore the role of these inflammatory mediators in regulating immunity to A. fumigatus. These studies will expand our understanding of how A. fumigatus conidia are typically controlled in immunocompetent mammals. With this detailed understanding of the sequel of events necessary for leukocyte recruitment and activation to prevent invasive aspergillosis we can better understand how steroid or chemotherapeutic treatment alters anti-Aspergillus immunity to allow fungal growth and disease and also therapeutically manipulate these pathways to benefit patients with invasive aspergillosis. We also study both inflammatory immunopathology induced by influenza virus in a virus strain-specific manner with the goal of elucidating the molecular mechanisms responsible for mast cell activation, recruitment, and activity during infection. We hope to elucidate the factor(s) which mast cells produce that drives pathological lung damage and systemic disease in hopes of discovering novel therapeutic targets.
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.
Benjamin D. Ross, Ph.D.
The bacteria resident in the human gastrointestinal tract (the gut microbiota) potently influence diverse aspects of human health, including immunity. However, the forces that govern the composition of the gut microbiota are poorly understood. Our work focuses on a mechanistic, ecological, and evolutionary understanding of how interbacterial interactions between members of the dominant Gram-negative bacteria in the gut, the Bacteroidales, modulate the composition of the microbiota. The Bacteroidales utilize a contact-dependent toxin-delivery system known as the type VI secretion system (T6SS) to kill neighboring cells. We study the impact of this pathway on the microbiota and how bacteria adapt to defend against T6SS-mediated antagonism, using a combination of bacterial genetics, biochemistry, metagenomics, and germ-free mouse models. We are also interested in understanding why Bacteroidales abundance is depleted in individuals with cystic fibrosis, with the goal of improving health through restoration of these bacteria.
Daniel Schultz, Ph.D.
Using both experimental and theoretical approaches, I investigate the process by which evolution optimizes antibiotic responses addressing evolutionary pressures requiring fast action (dynamical efficacy). By identifying the constraints and fitness costs that shape the evolution of response mechanisms, I explore how dynamic regulation strategies emerge and how they are implemented in terms of genes, promoters and operators.
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.
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.
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.
Olga Zhaxybayeva, Ph.D.
My research interests are to understand how microbes change over time. Recent advances in DNA sequencing technologies brought us an avalanche of data: thousands of genomes and terabases of environmental DNA (metagenomes). I mine these data sets to assess the impact of horizontal gene transfer on microbial populations, find new ways to characterize microbial communities, and track down genomic signatures of microbial adaptations.
Research-track faculty and emeritus faculty do not accept Ph.D. students.