The MMG faculty are members of numerous departments within the Emory University School of Medicine, the School of Public Health, and Emory College as well as the U.S. Centers for Disease Control. Click on a faculty member's name to get more information about them and their research.
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Larry Anderson, Ph.D.
Professor of Pediatrics, Division of Infectious Diseases
Pathogenesis of respiratory virus infections, especially respiratory syncytial virus and rhinovirus infections, to guide development of antiviral drugs and vaccines.
Pathogenesis of Respiratory Syncytial Virus (RSV) Disease. Our laboratory is focusing on pathogenesis of respiratory syncytial virus (RSV) disease related to vaccine development and anti-viral treatment. RSV is the single most important cause of serious lower respiratory tract disease in the infant and young children and a high priority for vaccine development. Unfortunately, efforts to develop RSV vaccines have failed. The first vaccine, formalin inactivated RSV (FI-RSV), actually led to enhanced disease when recipients were later infected with RSV. Multiple live virus vaccines have also been developed but none has proven safe and effective. These experiences suggest we need a better understanding of virus induced host responses associated with disease and those associated with protection. Our laboratory is using the BALB/c mouse and a human airway epithelial cell line (polarized and non-polarized cells) plus human peripheral blood mononuclear cell (PBMC) cell culture system to explore virus induced host responses that contribute to disease and ways to prevent these responses. For the last 10 years, we have focused much of this work on the RSV G protein and its CX3C chemokine motif. The G protein and this motif appear to contribute to induction of a Th-2 type T cell response and enhanced pulmonary inflammatory after RSV infection and FI-RSV vaccination. For example, administration of a monoclonal antibody that bind G near the CX3C motif and blocks binding to CX3CR1 before or after challenge decreases the pulmonary inflammatory response in naïve or FI-RSV vaccinated mice. A G peptide vaccine that induces antibodies that block binding to CX3CR1 also blocks the Th2-type pulmonary inflammatory response seen after RSV challenge in FI-RSV vaccinated mice. We are using G peptide vaccines, anti-G monoclonal antibodies, clinical RSV isolates associated with different phenotypes, and genetically engineered viruses to 1) understand pathogenesis of RSV disease and especially that associated with the G protein and 2) develop novel approaches to making a safe and effective RSV vaccine. Rhinovirus Infection and Asthma. Our laboratory is also looking at rhinovirus infection in children with asthma to understand immune responses associated with asthma and identify novel ways to treat rhinovirus induced asthma exacerbations. Asthma is a major cause of disease globally and associated with ~1.75 million asthma-related emergency department visits and ~456,000 asthma-related hospitalizations in the United States in 2007. Rhinoviruses are associated with approximately 50% of asthma exacerbations and provide a way to study the "asthmatic immune response" and opportunities to treat or prevent asthma exacerbations by treating rhinovirus infection. We are using rhinoviruses, enteroviruses (closely related to rhinoviruses but not associated with asthma exacerbations), human airway epithelial cells infected with rhinovirus and enteroviruses, and PBMCs from patients with and without asthma to identify 1) viral and host factors associated with asthma and 2) novel approaches to treat rhinovirus infections.
Pathogen Discovery. We are collaborating with a viral pathogen discovery program at the Centers for Disease Control and Prevention to improve and apply strategies to identify novel pathogens associated with disease. Strategies include pan-viral family PCR assays, high throughput sequencing and the bioinformatics needed to analyze the sequence data, and selective cloning and gene amplification.
Graeme Conn, Ph.D.
Associate Professor of Biochemistry
RNA Modification and Bacterial Antibiotic Resistance
We are studying a number of RNA methyltransferase enzymes that confer antibiotic resistance by specific chemical modification of RNA nucleotides within their bacterial ribosome drug binding sites. One of our major goals is to understand the protein-RNA recognition processes that determine the great specificity of target selection by these enzymes. Novel inhibitors that interfere with this unique aspect of resistance methyltransferase function may then be envisaged that could potentially extend the useful lifespan of current antibacterial agents.
Regulation of human PKR by viral non-coding RNAs and proteins
The double stranded (ds)RNA-activated protein kinase (PKR) is an important component of the host cell innate immune response to viral pathogens. The result of PKR activation by viral dsRNA or ribonucleoprotein complexes is the shut-down of protein expression, including that of viral proteins. Viruses counter this defense mechanism by producing non-coding RNAs or proteins that inhibit or sequester PKR. Our goal is to reveal the molecular mechanisms of PKR regulation by these viral RNAs and proteins.
In both projects, our lab uses a broad multidisciplinary experimental approach that incorporates molecular and microbiological methods, in vitro biochemical and biophysical analyses of enzyme activity and protein-RNA interaction, and structural studies using our state-of-the-art macromolecular X-ray crystallography facility.
Dr. Cynthia Derdeyn is investigating the targets and properties of neutralizing antibodies in early HIV-1 infection of African subjects, and the molecular mechanisms that the virus employs to escape from this immune response, in collaboration with scientists at Emory's RSPH. She is one of few investigators that has characterized the neutralizing activity of monoclonal antibodies from recently HIV-infected patients against their autologous viral variants. These studies have revealed that neutralizing antibodies initially target a single epitope that is unique to each infection, and that the antibody-antigen recognition mechanisms facilitate rapid viral escape. More recently, she has uncovered evidence that the early neutralization targets and viral escape pathways may set the course for whether an infected individual will develop of heterologous neutralization breadth later in infection. She is currently determining the structural and genetic properties of these evolving neutralizing antibodies in collaboration with investigators at the NYU School of Medicine. In collaboration with clinical investigators through the Emory CFAR, she has found that neutralizing antibody breadth persists later in the chronic stage of HIV infection despite widespread dysfunction and immune activation with the B cell compartment. Together these studies suggest that heterologous neutralization breadth is initiated in early infection, prior to its detection in vitro, and is dependent upon both viral and host events. She is also investigating how B cells and antibodies mediate vaccine-induced protection against an SIV challenge in nonhuman primates at Yerkes in collaboration with EVC investigators, as well as how depletion of CD4 T cells in SIV infection changes viral tropism and accelerates pathogenesis in collaboration with investigators at EVC and the University of Pennsylvania. Together, these studies should reveal information about how to induce antibody-mediated protection against genetically diverse variants of HIV with a vaccine.
Cynthia A. Derdeyn, Ph.D.
Associate Professor of Pathology and Laboratory Medicine
Ruben Donis, Ph.D./D.V.M.
Adjunct Professor of Pathology and Laboratory Medicine and
Influenza Section, Centers for Disease Control and Prevention
Molecular basis of influenza virulence and host switching; development
of broadly protective influenza vaccines.
Influenza is not an eradicable disease; the large pool of influenza in
birds allows periodic emergence of pandemic viruses. Pandemics such as
the 1918 Spanish influenza were major public health catastrophes. The
major emphasis of our research is to understand the host range and
pathogenicity of influenza in avian and mammalian hosts to design public
health intervention strategies that mitigate the impact of pandemic and
seasonal influenza. The fundamental premise or our work is that novel
prevention or therapeutic interventions will require knowledge of the
molecular mechanisms of disease and host protection. This is why we
design studies to link the molecular structures and functions of virus
and host to the mechanism of disease development. Our current research
(1) Studies on viral determinants of influenza host range and virulence.
We use genetically engineered viruses to analyze the functions of the
two major categories of viral proteins; 1a) hemagglutinin and
neuraminidase surface proteins are being studied in glycan arrays, and
receptor binding assays; 1b) viral replication complex proteins are
currently studied by proteomics, microarray, and cell biology
(2) Structural studies to understand how protein structure affects
glycan binding specificity of the viral hemagglutinin and neuraminidase
proteins. These studies are complemented by in vivo experiments to
explain mechanisms of interspecies transmission and virulence.
(3) Studies to understand the emergence of pandemic influenza by viral
gene reassortment exploiting reverse genetics and organismal approaches.
This research is revealing interesting novel functional properties of
potentially pandemic strains.
(4) Development of novel vaccines for epidemic and pandemic influenza.
We analyze the structural basis of antigenic drift of the hemagglutinin
to develop structure-based immunization approaches that expand the
breath of the neutralizing antibody response to seasonal and pandemic
Our studies are expected to discover novel approaches to assess the risk
of interspecies transmission of influenza viruses and their severity as
well as provide novel vaccines for prevention of influenza.
Mary Galinski, Ph.D.
Professor School of Medicine: Infectious Diseases
Research Interests: Dr. Galinski started a Malaria Research Program at Emory beginning at the time of the opening of the vaccine center premises in 1999. This highly successful program has grown rapidly in its first five years at the Emory Vaccine Center. Dr. Galinski and her colleagues have been known internationally for their discoveries of several P. vivax and P. falciparum merozoite vaccine candidates, basic studies of simian malaria models, and investigations of the molecular mechanisms that underpin antigenic variation. Dr. Galinski brought these major lines of research to Emory and has since expanded her program to include pathogenesis, epidemiology and vaccine testing components. She also facilitated the development of the current broad-based multi-investigator malaria research effort at the Emory Vaccine Center.
Justin Gallivan, Ph.D.
Associate Professor of Chemistry
Our research program has two major foci: we use synthetic biology to engineer organisms with useful properties; and we engineer molecules and organisms to help elucidate fundamental biological principles. Much of our work involves riboswitches, which are RNA sequences that regulate gene expression in a small-molecule dependent fashion, without the need for protein cofactors. Our lab has pioneered new methods to create synthetic riboswitches, and we have used them to endow cells with novel behaviors (for example, the ability to follow small molecules). In collaborative work, we have been using synthetic riboswitches as inducible genetic control elements to study pathogenic bacteria, such as A. baumannii (a multidrug-resistant pathogen), F. tularensis (the causative agent of tularemia "rabbit fever" and a potential bio-warfare agent, and M. tuberculosis (a bacterium that is the 2nd leading cause of deaths worldwide, and the leading contributor to deaths by a treatable infection). For more details, please visit our website: http://www.gallivanlab.org
Joanna Goldberg, Ph.D.
Professor of Pediatrics
The synthesis and regulation of bacterial surface polysaccharides and other potential adhesins, and their effect on virulence and physiology in order to develop rational strategies to disrupt pathogenesis.
My laboratory investigates the strategies used by bacteria to cause diseases in humans. We study various bacteria and their factors especially surface polysaccharides and other potential adhesins, and assess their effect on the virulence and physiology of the bacterium, as well as on host cells. Our general approach is to perform genomic analysis, construct, and characterize bacterial mutants, and monitor these for relevant phenotypic and genotypic attributes and both in in vitro and in vivo models of infection. The long-term goal of this work is to devise rational methods to the disrupt virulence and promote clearance of infecting bacteria.
Pseudomonas aeruginosa is a Gram-negative bacterium that is ubiquitous in the environment.
Arash Grakoui, Ph.D.
Associate Professor of Infectious Disease and Microbiology and Immunology
Hepatitis C virus (HCV)
Hepatitis C virus (HCV) infection is a growing public health problem affecting 170 million people worldwide (~3 million in the United States). While twenty percent of patients infected with HCV are able to clear the infection after several months, the majority of patients become chronic carriers who, in addition to being the source for most new infections, can progress to chronic active hepatitis with cirrhosis and/or hepatocellular carcinoma (HCC). These clinical sequelae of HCV infection now comprise the leading indication for liver transplantation in the United States and account for 8-10,000 deaths each year in the United States alone. Despite its grave clinical consequences (i) no vaccine exists to prevent HCV infection and (ii) the only licensed therapy (alpha interferon (IFN_), either alone or in combination with the nucleoside analog ribavirin) for chronic HCV infection is expensive, associated with poor response rates, and laden with significant side effects. The paucity of efficacious anti-HCV therapeutic options highlights the need for effective interventions aimed at augmenting or supplementing the natural immune response and that alone or in concert with drug therapy can prevent the detrimental consequences of HCV infection. Development of such successful intervention strategies requires a thorough understanding of the host determinants of infection resolution.
Our previous work has established the importance of the memory CD4+ T cell response in HCV infection resolution and prevention of viral escape as well as confirmed the importance of intrahepatic CD8+ T cells in viral elimination. Our laboratory is now focused on four main project areas utilizing murine, human and non-human primate experimental systems:
- To understand the role of regulatory T cell populations and NKT cells in facilitating HCV persistence and to define the functional and phenotypic differences between HCV-specific T effector cell populations in acute and chronic infection.
- To determine whether functional differences in HCV antigen presentation contribute to viral persistence.
- To define the impact of HIV co-infection on anti-HCV immune responses.
- To optimize antigen delivery systems utilizing antibody engineering as a vaccine strategy to optimally stimulate an anti-HCV immune response.
Murali Krishna Kaja, Ph.D.
Acting Associate Professor of Infectious Diseases
The goal of experiments in the Kaja laboratory is to understand the mechanisms by which innate and adaptive immune systems interact together in response to infection and generate the most efficient protective immune memory. Lessons learned from such experimental models will be useful for rational and refined vaccine design. The projects in the lab are specifically focused on understanding how type-I interferons, a set of inante anti-viral cytokines that are induced in the first few hours after infection, influence the generation and maintenance of pathogen specific cytotoxic and helper T cell responses.
Daniel Kalman, Ph.D.
Associate Professor of Pathology and Laboratory Medicine
Mechanisms by which pathogens cause cytoskeletal & signaling changes in pathogenesis.
The general goal of our laboratory is to understand how bacterial and viral pathogens interface with the host. We have focused on two mechanistic aspects of this interface: (i) the immunological detection and clearance of the infection, and (ii) host systems utilized by the pathogen to facilitate infection. Our work has focused on four pathogens: enteropathogenic E.coli (and the related enterohemmorhagic E. coli, the cause of "raw hamburger disease), vaccinia virus (a relative of variola virus, the cause of smallpox), Polyomaviruses, and Mycobacteria tuberculosis. We have utilized a combination of experimental approaches including cell biology assays based on high resolution deconvolution microscopy, biochemical systems that permit reconstitution of cellular responses with cytoplasmic extracts in permeablized cells, mouse genetic systems that model human disease, and permit investigation of the immunological response to the pathogen, and a C. elegans model system which allows genetic dissection of both host and pathogen. A long-term goal of the laboratory is to develop approaches that will permit identification of agents useful in treating disease. There is considerable impetus for developing such agents to treat infections caused by bacterial and viral pathogens: development of resistance to antibiotic or other chemotherapies looms as perhaps the single most important public health concern confronting humans in the coming century. In this regard, our current efforts have led to the development and testing of novel inhibitors of pathogenic E.coli and poxvirus infections infections (e.g Reeves et al., Nature Medicine 11:731-739), which interfere with the interface between host and pathogen but not with microbial growth. As such, these inhibitors will not easily engender development of drug resistance.
Baek Kim, Ph.D.
Director, Center for Drug Discovery and Professor of Pediatrics
Elucidate the enzymatic mechanisms and molecular players involved in replication and evolution of HIV-1 and other RNA viruses such as influenza virus and to search for new anti-viral target mechanisms.
Our laboratory has been working on the molecular and cellular biology of HIV-1 replication, mutagenesis, evolution and viral escape by employing both biochemical and virological approaches. Recently, we have launched new projects designed to understand cell signal pathways that are hijacked by HIV-1 for the establishment of long-living HIV-1 macrophage reservoirs. We also focus on understanding the cellular metabolic changes made by HIV-1 infection for maintaining long-term survival of macrophage reservoirs and persistent viral production.
In addition, through the support of the New York Influenza Center of Excellence, our laboratory began exploring the mechanisms involved in the replication and mutagenesis of swine and avian influenza viruses, which contribute to viral host switch and adaptation between animals and humans. The titles of the current research subjects in the Kim laboratory are:
1) Mechanistic understanding of highly error prone HIV-1 reverse transcriptase
2) Cell type-specific HIV-1 mutagenesis and evolution
3) Long-living HIV-1 macrophage reservoirs and PI3K/Akt cell survival pathway
4) Metabolomics of HIV-1 macrophage and resting memory T cell reservoirs
5) Kinetic and mechanistic analysis of influenza virus replication machinery
Tracy Lamb, Ph.D.
Assistant Professor of Pediatrics, Division of Infectious Diseases
Generation of immune responses to malaria parasites; immunopathogenesis of malaria infections; development of a novel vaccine delivery system to vaccinate against malaria
Dr. Lamb's research focuses on understanding the immunology of malaria infections with a view to rational malaria vaccine development. The immune response to malaria parasites can directly contribute to the pathology observed in malaria infection (for example see Lamb and Langhorne, Malaria Journal 2008). Therefore it is important that a vaccine against malaria is able to induce an immune response that clears malaria parasites from the body without inappropriate or excessive inflammation and immunopathology. To make a vaccine, it is necessary to understand how immune responses to malaria are initiated in malaria infection, and also to identify the features of a desirable immune response that should be replicated by a vaccine to provide protection. The Lamb lab is interested in defining how different populations of CD4+ T helper cells arise in malaria infection because CD4+ T helper cells are generally considered to orchestrate immune responses in the body. Malaria infection is associated with an inflammatory response characterized by the expansion of CD4+ Th1 cells that produce interferon-γ; this response activates immunological mechanisms to clear malaria parasites from the body but, when over-exuberant, also contributes to the pathogenesis of malaria infection. CD4+ T cells that produce the immunoregulatory cytokine interleukin-10 also expand in malaria infection; IL-10 producing CD4+ T cells are crucial in providing protection against malaria-induced immunopathology. Given the importance of CD4+ Th1 cells that produce interferon-γ and CD4+ T cells that produce interleukin-10 in determining the outcome of malaria pathogenesis and infection (Meding et al., Infection and immunity 1990; Couper et al., PLOS Pathogens 2008), the Lamb lab are investigating the molecular cues that lead to the expansion of these two phenotypes of CD4+ T cells. We study how antigen presenting cells (such as dendritic cells) respond to malaria parasitized red blood cells - complex structures containing many different antigenic determinants (see Lamb et al., Future Microbiology 2010). Current studies are focused on 1. Determining the signaling pathways triggered in antigen presenting cells exposed to malaria-parasitized red blood cells 2. Elucidating the role of the Ephrin / Eph kinase family of molecules in co-stimulation of CD4+ T helper cells in malaria infection 3. The development of a novel oral vaccine delivery system aimed at generating immune responses against malaria parasites.
Anice Lowen, Ph.D.
Assistant Professor of Microbiology and Immunology
The underlying mechanisms governing two processes critical to the evolution and epidemiology of influenza viruses: inter-host transmission and the reassortment of gene segments.
Despite its clear importance to the epidemiology of influenza, the process by which human influenza viruses travel from one individual to another is not well understood. The lack of transmission of H5N1 influenza viruses among humans and other mammals has shown that, contrary to expectation, viral growth is not the only prerequisite for transmission. Research over the past six years has revealed that viral, host and environmental factors each play a role in determining the efficiency with which an influenza virus transmits. We previously showed, for example, that humidity and temperature have a strong impact on the efficiency of transmission, that host-specific adaptive changes in the viral polymerase can alter transmission efficiency, and that host immunity resulting from vaccination or natural infection limits transmission to varying degrees. Despite such progress, an in-depth understanding of transmission remains a high priority in the influenza field. Going forward, my research will focus on the viral traits which allow transmission to proceed in guinea pigs, a mammalian model system which we have demonstrated to reflect humans well in terms of influenza virus transmissibility. Reassortment is the process by which influenza viruses, which carry RNA genomes comprising eight segments, exchange genetic material. Reassortment of the genome segments of two differing influenza strains has the potential to vastly increase the diversity of circulating influenza viruses. Despite its importance to influenza virus evolution, the frequency with which reassortment occurs in an animal infected with two or more variant viruses is unclear. I therefore propose to assess the incidence of reassortment in experimentally infected guinea pigs. By studying the process under well-controlled conditions, I aim to identify factors which dictate how readily reassortment can occur. For example, the roles of pre-existing immunity to one subtype, sequential rather than coincident infection, genetic compatibility between differing viruses, and the likelihood of two distinct strains to infect the same cell type will be studied.
David Lynn, Ph.D.
Howard Hughes Medical Institute Professor, Asa Griggs Candler
Professor of Chemistry & Biology Professor and Chair of Chemistry
Dave Lynn's group at Emory University works to understand the
structures and forces that enable supramolecular self-assembly, how
chemical information can be stored and translated into new molecular
entities, and how the forces of evolution can be harnessed in new
structures with new function. Such knowledge offers tremendous promise
for discoveries in fields as diverse as drug design and genome
engineering, pathogenesis and genome evolution, functional nanoscale
materials and the origins of living systems.
In the context of pathogenesis, Agrobacterium tumefaciens occupies a
special place in the laboratory. This soil-borne alpha-proteobacterium
has the capacity to transfer DNA from a resident tumor inducing (Ti)
plasmid into eukaryotic cells where the oncogenic DNA (T-DNA) is
integrated into the host genome and expressed. It is the only organism
known to routinely engage in lateral gene transfer between Kingdoms,
and the molecular basis of this transformation process has had
considerable impact on studies of lateral DNA transfer and integration.
In the case of Agrobacterium, virulent bacteria recognize signals
produced at a host wound, phenols, monosaccharides, and low pH, as cues
inducing expression of the Ti-encoded virulence (vir) genes. The vir
gene products, among other functions, are necessary for the processing
and transport of the T-DNA from the bacterium to the eukaryotic cell.
We have employed biochemical and molecular genetic methods to develop a
mechanism for the signal transduction process, revised models for
signal perception, and are attempting to move the DNA transfer
machinery to heterologous hosts.
McBride, Shonna, Ph.D.
Assistant Professor of Microbiology and Immunology
Molecular mechanisms of bacterial pathogenesis; Bacterial defense against antimicrobial peptides; Gastrointestinal pathogenesis
Our laboratory is focused on identifying and understanding the mechanisms that pathogens utilize to colonize and persist within the gastrointestinal environment. In particular, we are interested in understanding the genetic mechanisms used by the pathogen Clostridium difficile to subvert host defenses and survive within the mammalian intestine. To colonize the intestine and cause persistent infections, C. difficile must be able to circumvent killing by host innate immune defenses. The production of cationic antimicrobial peptides (CAMPs) by the host and the indigenous microbiota represent a critical component of host defense against infections that bacteria must overcome to cause persistent disease. We have evidence that resistance of C. difficile to antimicrobial peptides plays a major role in the ability of the bacterium to colonize the human intestine and cause disease. As such, our laboratory is focused on identifying and understanding the mechanisms that C. difficile utilizes to resist CAMPs produced by the host and the indigenous microbiota of the intestine. To date, we have identified multiple CAMP resistance mechanisms employed by C. difficile, including the novel bacteriocin resistance mechanism, CprABC. By uncovering the bacterial resistance mechanisms that influence disease progression, it is expected that this research will generate knowledge that can be used to manipulate the interactions between the bacteria and the host to prevent and treat infections.
McBride, S.M. and Sonenshein, A.L. (2011). The dlt Operon Confers Resistance to Cationic Antimicrobial Peptides in Clostridium difficile. Microbiology; May;157(Pt 5):1457-65. Epub 2011 Feb 17. PMCID: PMC3140582
McBride, S.M. and Sonenshein, A.L. (2011) Identification of a Genetic Locus Responsible for Antimicrobial Peptide Resistance in Clostridium difficile. Infect Immun; Jan;79(1):167-76. Epub 2010 Oct 25. PMCID: PMC3019887
Gregory Melikian, Ph.D.
Professor of Pediatrics, Division of Infectious Diseases
The molecular mechanisms of enveloped virus entry into cells.
Our laboratory studies the molecular mechanisms of enveloped virus entry into cells. When activated by binding to cellular receptors and/or by acidic pH in endosomes, viral fusion proteins undergo extensive conformational changes resulting in membrane merger. Current projects involve function studies of fusion proteins of influenza virus, Human Immunodeficiency Virus (HIV) and other retroviruses, as well as Hepatitis C Virus (HCV). By imaging individual virions co-labeled with fluorescent membrane and content markers, we visualize the lipid mixing (hemifusion) and the fusion pore formation steps in live cells. We have recently showed that HIV, which has long been thought to infect host cells by direct fusion with the plasma membrane, enters permissive cells via endocytosis and pH-independent fusion with endosomes. These findings provide a new paradigm for HIV entry and suggest alternative strategies to block infection. We also study the entry mechanisms of low pH-dependent viruses, influenza and Avian Sarcoma and Leukosis Virus (ASLV). ASLV Env glycoprotein is first primed by interactions with a cognate receptor at the cell surface, which renders Env competent for low pH-induced conformational changes and fusion with acidic endosomes. Sequential priming and triggering of ASLV fusion and the virus' ability to utilize two naturally occurring isoforms of the cognate receptor is essential for dissecting the virus entry pathways. Our work on the mechanism of HCV fusion involves the usage of soluble receptor fragments and low pH to trap transient states of the HCV E1E2 glycoproteins en route to fusion with acidic endosomes. We have shown that one of the four essential receptors, CD81, renders HCV competent for low pH-mediated fusion within endosomes. Another project in the laboratory is aimed at understanding the anti-viral activity of human defensins, highly charged cationic peptides capable of blocking entry of HIV and other viruses. We are currently applying quantitative imaging and spectroscopy methods to better understand virus trafficking and fusion, as well as to delineate the role of receptor signaling in infection. We are also interested in reconstituting viral fusion in a supported lipid bilayer system and carrying out mechanistic studies of this process on a single-molecule level.
Edward Mocarski, Ph.D.
Robert F. Woodruff Professor and
Professor of Microbiology and Immunology
Dr. Edward Mocarski is currently the Robert W. Woodruff Professor of
Microbiology and Immunology, and member of the Emory Vaccine Center.
Dr. Mocarski studies the replication, latency and host response to
herpesviruses, specializing in cytomegalovirus, an important
opportunistic pathogen in immunocompromised hosts. Dr. Mocarski,
together with the students and postdoctoral fellows he has helped
train, has made significant discoveries into how cytomegaloviruses
regulate gene expression, replicate their genomes, mature and spread
during replication. He has explored the pathogen:host stand-off,
investigating immunomodulatory viral functions as well as the
properties of latency and reactivation that are central to viral
pathogenesis. With collaborators, he has investigated chronic disease
complications of cytomegalovirus infections. Dr. Mocarski's research
has yielded targets for anti-viral therapies as well as information
critical to vaccine initiatives.
Martin Moore, Ph.D.
Assistant Professor of Pediatrics, Division of Infectious Diseases
Mucogenic Respiratory Syncytial Virus (RSV) Strains: Pathogenesis and Reverse Genetics
RSV is the leading cause of bronchiolitis, viral pneumonia, and viral death in infants. RSV is the leading cause of respiratory failure and mechanical ventilation in infants. There is no RSV vaccine in use and no widely available therapies. RSV is not only a scourge of infancy but also a major cause of asthma exacerbations in children and adults, and a major cause of pneumonia in the elderly.
Airway mucus is a hallmark feature of RSV lower respiratory tract infection. Mucus, necrotic epithelial cell debris, and inflammatory cells obstruct the airways, leading to characteristic wheezing and respiratory failure in severe cases.
We identified and derived strains of RSV that exhibit differential disease phenotypes in mice. Some RSV strains induce high levels of the cytokine IL-13, airway mucus, severe histopathology, and pulmonary obstruction, whereas other strains induce a more protective TH1-type response.
The primary focus of my laboratory is to define mechanisms of RSV immunopathogenesis and investigate the role of RSV strain differences in differential RSV pathophysiology. We are using differentially virulent RSV strains and a RSV reverse genetics system to dissect molecular mechanisms leading to airway mucus expression, bronchiolitis, and pulmonary obstruction in the mouse model. These studies may lead to much-needed effective vaccines and/or therapies for RSV disease.
A comprehensive understanding of how RSV strain differences affect pathogenesis and immunity will require bridging gaps between basic research, epidemiology, and clinical studies.
website: The Moore Laboratory
Charles P. Moran, Ph.D.
Professor of Microbiology and Immunology
Microbial genetics; gene expression during bacterial differentiation, RNA polymerase-promoter interactions.
The work in our laboratory focuses on the control of gene expression during bacterial differentiation. Asa the bacterium Bacillus subtilis differentiates from the vegetative form into a dormant endospore, complex morphological and physiological changes occur that require the expression of many genes. During the process, new RNA polymerase sigma subunits appear (oF, oE, oG, oK), displacing one another and conferring on the RNA polymerase different specificities for the recognition of different classes of promoters. One focus of our laboratory is to elucidate the mechanisms that regulate sigma factor function. For example, the DNA binding protein SpoOA responds to environmental signals by activating the transcription of several key operons at the onset of sporulation. We are currently testing the model in which SpoOA, when bound to promoter DNA, interacts directly with the RNA polymerase sigma subunit. We are also studying an example of regulation of gene expression by a morphological cue. During sporulation B. subtilis divides into two compartments (forespore and mother cell) that follow different developmental paths. Forespore-specific transcription is initiated by oF-RNA polymerase, and results in the forespore-specific production of oG, which directs the subsequent forespore-specific transcription. However, oG does not become fully active until engulfment of the forespore is completed. We want to know how the activity of oG is coupled to this morphological change. We have shown that the anti-sigma factor SpoIIAB may play an important role, and now we are attempting to identify additional genes whose products regulate oG activity. The utilization of gene products during the assembly of the complex morphological structures of the spore is governed both by the order of their synthesis, and by the order of their assembly into these structures. It is not known how these two mechanisms are coordinated. Transcription of several genes encoding spore coat proteins is directed by oK, the last o of the cascade. However, premature synthesis of spore coat proteins does not result in the premature assembly of spore coat-like structures. We are attempting to elucidate the mechanisms that regulate the utilization of spore coat proteins.
Guey Chuen (Oscar) Perng, Ph.D.
Associate Professor of Pathology and Laboratory Medicine
Pathogenesis of chronic virus infections, focusing on the early immune events upon viral-host contacts.
Three programs are initiated to tackle the mechanisms by which diseases developed in the course the host responses to the virus infections.
HSV-1 can cause encephalitis in infected animals and humans. Although herpes encephalitis is rare in adults, it affects 2-5% of infected infants and is therefore of significant clinical importance.
Following peripheral infection, HSV-1 establishes latency in neurons of the infected host. Sporadically, the latent virus resurfaces to the sites of initial infection, causing recrudescent disease. The only gene that is readily detectable during neuronal latency is latency associated transcripts (LAT). We have shown that LAT locus is involved in neurovirulence in experimentally infected animals. Deletion of different portions of the LAT locus can alter the rate of death of infected animals due to encephalitis. Recently, we have cloned and demonstrated a gene, UOL (Upstream of LAT), locating in the LAT locus region plays a role in virulence in infected animals. Further studies indicated that the UOL interacts with an immune regulator factor, ICAM5, in the central nervous system (CNS). This interaction alters immune response in herpes infected animal brains. Identification of the mechanisms involved in the pathogenesis of encephalitis is of particular importance, given the current concerns of emerging infections and bioterrorism threat.
Herpes Stromal Keratitis (HSK) results from the infection of HSV-1 in cornea. HSV-1 infection, mainly recurrent, is a leading cause of corneal scarring and visual loss. HSK is characterized with tissue destruction, edema, opacification, corneal scarring, and neovascularization, and is thought to arise from an immunological inflammatory response in the stroma layer of cornea. However, no specific HSV antigens or peptides are physically demonstrated from the HSK corneas. Thus the cause of HSK is unclear.
Recently, we reported that in HSV-1 induced HSK rabbit corneal buttons, an immediate early protein ICP0 was consistently detected in the water-soluble corneal extract and in the tears of infected animal eyes. To our surprise, the presence of ICP0l in the corneal was coincident with the loss of suggestive structural protein, Aldehyde dehydrogenase 1 (ALDH1). In wound injury in vivo animal models, the markedly reduced levels of ALDH1 correspond to the development of corneal opacity. By focusing on studying, identifying, and characterizing the molecular marker, HSV immediate early protein ICP0 and its relation to ALDH1, the pathogenesis of HSK may be comprehensible and may lead to develop a new treatment for the bothersome disease.
Dengue Hemorrhagic Fever (DHF)/Dengue Shock Syndrome (DSS)
Dengue fever, caused by infection with dengue virus, is not a new disease, but recently its serious emerging health threats, coupled with possible dire consequences including death, has aroused considerable medical and public health concern worldwide. The main obstacle for diagnosis is the dynamic spectrum of dengue illness ranging from asymptomatic to dengue hemorrhagic fever (DHF/dengue shock syndrome (DSS), characterized by thrombocytopenia and increased vascular permeability.
One of the hallmarks in dengue disease is thrombocytopenia otherwise known as low platelet counts. The degree of thrombocytopenia appears well-correlated not only with the clinical severity of DHF but also with the activation of the complement system.
During dengue virus infection, platelets may provide a wonderful shield for the virus from exposure and binding to neutralizing preexisting antibody. Interestingly, there are a few reports suggesting that dengue virus may associate with platelets, directly or indirectly through antibody. Recently dengue virus RNA has been detected in platelets isolated from dengue infected patients using RT-PCR techniques. The interesting point in these observations or reports is that the thrombocytopenia seen in DHF/DSS patients may not only be due to the destruction of platelets by the virus itself (direct cytotoxicity) but may also be due to the destruction of platelets following the binding of dengue specific antibodies to the virus infected platelets (immune mediated toxicity). It is also possible that platelets can serve as a reservoir for dengue virus replication; however this issue is a subject of further investigation. By investigation the role of platelets in the course of dengue virus infection may shed a new insight to the pathogenesis of dengue disease, new treatment, and a new strategy in vaccine development.
Richard K. Plemper, Ph.D.
Associate Professor of Pediatrics
Paramyxovirus Entry, Replication and Development of Innovative Antiviral Therapeutics
Paramyxoviruses, enveloped, negative strand RNA viruses, cause significant morbidity and mortality worldwide. My lab studies paramyxovirus entry and replication with the ultimate goal to open novel antiviral avenues. Major research projects of the lab include:
Structure-function analysis of native paramyxovirus envelope glycoprotein complexes
Protein-mediated membrane fusion at neutral pH is employed by a variety of viral families to gain cell entry and is essential for eukaryotic cell organization. Members of the paramyxovirus family typically rely on the concerted action of two envelope glycoproteins to achieve membrane fusion for viral entry. Despite their major clinical importance, many of the mechanistic principles that govern the organization of metastable paramyxovirus fusion complexes and their coordinated refolding remain poorly understood. Towards the overall goal of elucidating these principles, my lab studies the envelope proteins of measles virus, an archetype of the paramyxovirus family, to address three fundamental questions: What is the spatial organization of viral glycoprotein hetero-oligomer complexes in the native, metastable prefusion conformation displayed on infectious particles? How does receptor binding affect this organization? What is the nature of the intermolecular contacts that link receptor binding with refolding of the complexes into the stable postfusion conformation?
We hypothesize that prefusion MV glycoprotein hetero-oligomers assume a tightly packed spatial organization on the surface of infectious particles, that receptor binding alters the oligomeric status of the attachment protein, and that this affects specific residues at the hetero-oligomer interface resulting in F refolding. The lab applies molecular virology, reverse genetics biochemistry, microchemistry, imaging and molecular modeling techniques to test these hypotheses in a comprehensive approach.
Small-molecule inhibitors of the paramyxovirus RNA-dependent RNA-polymerase
It is the overarching goal of this project to develop small-molecule blockers of the paramyxovirus RNA-dependent RNA-polymerase (RdRp) complex. A recent trend of declining public acceptance of measles vaccination has fueled a resurgence of the virus in several industrialized countries. We hypothesize that a joint anti-measles platform consisting of prophylactic (vaccination) and therapeutic (antivirals) components will improve case management and block virus spread in areas with insufficient vaccination coverage. Indeed, a first feasibility study has targeted the RdRp of measles virus to augment existing vaccination for global measles control.
Through structure-guided drug design and high-throughput screening, we have identified a first-in-class non-nucleoside inhibitor of the paramyxovirus RdRp. The lead compound shows good oral bioavailability and in vivo half-life in pilot pK analysis. To test our hypothesis, the lab is advancing a subset of therapeutic lead analogs towards formal GLP development. In parallel, we employ molecular virology, microchemistry and molecular modeling technologies to elucidate the binding pose of this scaffold to RdRp. Extracting a pharmacophore will establish the foundation to tailor this potent chemical scaffold against RdRp complexes of other negative strand RNA viruses of the myxovirus families.
Exploring host-directed antivirals to counteract myxovirus (influenza, paramyxovirus) infection
Traditional, pathogen-directed antiviral approaches are often compromised by the development of viral resistance in the field. To address the problem of viral escape from inhibition conceptually, we pursue in this project an antiviral strategy that targets host cell components exploited by the pathogen for replication. In addition to a heightened barrier against resistance, this strategy has high potential to yield therapeutics with a broadened target range, moving beyond conventional "one-bug one-drug" approaches. Pathogens causing acute disease, as in the case of most myxovirus (influenza, paramyxoviruses) infections, are ideal targets since treatment time, and thus potential side effects of long-term host exposure to the drug, remain limited.
In this proof-of-concept project, we have identified a lead class of host-directed myxovirus inhibitors through high-throughput screening. This scaffold shows exquisite activity against different ortho- and paramyxoviruses, and thus provides a solid platform to evaluate the strategy conceptually. To test our central hypotheses, we will characterize the mechanism of antiviral activity, improve potency and drug-like properties, determine biotoxicity and efficacy, and explore whether viral resistance can eventually be induced.
Jyothi Rengarajan, PhD
Assistant Professor of Infectious Disease
Host-pathogen interactions in Tuberculosis
We are interested in understanding how pathogens evade host immunity and how the immune response combats pathogens. Mycobacterium tuberculosis is one of the world's most successful human pathogens and is responsible for the deaths of up to 3 million people annually. The AIDS pandemic and Multi-drug resistant TB, further underscore the global public health challenge that TB presents. Developing vaccines and better therapeutics for TB is thus an important goal in our research efforts.
The major questions that we seek to address in the lab are: How does M. tuberculosis survive in the host? Why does the host fail to eliminate M. tuberculosis? A fundamental concept that encompasses both these questions involves the M. tuberculosis-macrophage interface. Macrophages are central to host defense against microbes, but M. tuberculosis has evolved to evade their anti-microbial functions. We have used functional genomics to comprehensively determine the genome-wide requirements for M. tuberculosis survival and adaptation in macrophages by identifying mutants with defective intracellular growth. These studies also highlighted genes that are critical for pathogen survival and adaptation to the host, for example, a cell envelope-associated protease that modulates host innate immune responses. We are investigating the molecular and biochemical basis for protease function and have identified potential substrates using mass spectrometry-based proteomics approaches.
Other projects in the lab are focused on dissecting the molecular pathways involved in the host innate immune response to infection in macrophages and dendritic cells. We also have ongoing interests in understanding mechanisms of drug resistance in mycobacteria and identifying targets for new chemotherapeutics. In the long term, we are interested in translating lab-based findings to human population-based settings of tuberculosis infection. Human studies are important for understanding mechanisms underlying host susceptibility, latent infection and protective immunity.
Raymond F. Schinazi, Ph.D., DSc (hon)
Francis Winship Walters Professor of Pediatrics and Director, Laboratory of Biochemical Pharmacology
The LOBP develops approaches to treat infections caused by human immunodeficiency viruses, herpesviruses, HBV, HCV, and Dengue virus. These treatments include antiviral agents as well as synthetic, biochemical, pharmacological, and molecular genetic approaches, including molecular modeling and gene therapy. The laboratory's primary objective is to preclinically develop in-house compounds to prevent and treat these important pathogens. Of particular interest are the phenotypic and genotypic characterization of drug-resistant virus variants, as well as ways to overcome resistant viruses using combinations of antiviral drugs. Five compounds have gone to advanced clinical studies, and three of those have been approved by the US FDA. The lab also develops treatments for the protozoa Cryptosporidium parvum. This work involves animal models (SCID mice), cell culture methods, and molecular approaches (e.g., DNA library construction, sequencing) to identify targets unique to this organism.
Thomas M. Shinnick, Ph.D.
Adjunct Professor of Microbiology and Immunology
Associate Director for Global TB Laboratory Activities, DTBE/NCHHSTP of CDC
Molecular genetic analysis of Mycobacteria.
Tuberculosis and leprosy are important human disease that afflict more than 50 million individuals world-wide. The etiologic agents of these diseases are Mycobacterium tuberculosis and Mycobacterium leprae, respectively. Both of these mycobacteria are intracellular pathogens that grow within cells of the host immune system, primarily macrophages. Relatively little is known about the genes and gene products required for intracellular survival. Our research in this area concentrates on development and application of biophysical and genetic tools and strategies to identify mycobacterial genes that play roles in intracellular survival and replication. Current projects include using promoter-trap vectors and microarray hybridization approaches to identify differentially expressed genes.
We are also taking advantage of the recently published genome sequence of M. tuberculosis to direct studies to characterize gene expression in tubercle bacilli. Two-component global regulatory systems and sigma factors are being studied to elucidate details of the regulation of gene expression and characterize patterns of gene expression. The ultimate goal is to elucidate the mechanisms that underlie the transition from an active infection to a latent infection and from a latent infection to an active infection.
Samuel H. Speck, Ph.D.
Georgia Research Alliance Endowed Professor of Microbiology and Immunology
Pathogenesis of gamma-herpesviruses and development of lymphoma and other cancers.
The research in my lab focuses on 2 gamma-herpesviruses, Epstein-Barr virus (EBV) and murine gamma herpesvirus 68 (gHV68). A major property of all herpesviruses is their ability to persist for life in the infected individual. The gamma-herpesviruses are known to latently infect either B or T lymphocytes, and to be associated with the development of lymphoma and lymphoproliferative diseases. Our major interests are to understand: (i) how these viruses regulate viral gene expression during latency; (ii) how they modulate and avoid the host immune response; and (iii) how they switch from a latent infection to replication of the viral genome (referred to as reactivation), a process that is essential for propagation of these viruses to uninfected individuals. EBV is the etiologic agent of infectious mononucleosis and is closely associated with the development of Burkitt's lymphoma, nasopharyngeal carcinoma, 30-50% of Hodgkin's disease, and 50% of lymphomas that arise in immunosuppressed individuals (e.g., transplant patients and AIDS patients). Our research on EBV focuses on tissue culture models that recapitulate the various EBV genetic programs. The information gained from these studies is then employed to address the behavior of EBV in infected individuals. However, because there are no small animal models for studying EBV pathogenesis, we use gHV68 infection of mice to address specific issues of the host response to gamma-herpesvirus infection. The advantage of the latter model is that both the host and pathogen can be genetically manipulated to address fundamental aspects of host-pathogen interactions. gHV68 infection of mice causes several different chronic diseases in immunocompromised mice, including a severe vasculitis that affects the great elastic arteries and lymphoproliferative disease. We are currently identifying gHV68 genes involved in establishing and maintaining viral latency, as well as those involved in the development of chronic disease. In addition, we are actively characterizing the host response to viral infection to address how viral latency and persistent infection is controlled.
John Steel, Ph.D.
Assistant Professor of Microbiology and Immunology
Development of influenza virus vaccines; elucidation of molecular determinants of influenza virus transmission
As a Microbiology and Immunology faculty member at Emory University, my research interests include the development of broadly protective vaccines targeting influenza A viruses, and the identification of virally encoded molecular determinants of transmissibility of influenza viruses among mammals.
Broadly protective influenza vaccines The problem that we propose to address is the construction of a single vaccine that could protect against epidemic influenza A viruses arising over several decades and also against pandemic influenza, regardless of the virus subtype. The goal of generating a universal vaccine represents a significant challenge due to the massive diversity and rapid evolution of influenza A viruses The potential impact of a universal influenza vaccine would be huge. The successful implementation of our strategy would vastly reduce the impact of influenza on human health, and point the way toward the development of vaccines for other important viral pathogens. My previous research has shown that a modified influenza A virus hemagglutinin (HA) protein that includes the conserved stalk region, but lacks the highly variable and immunodominant globular head domain induces a protective response to a homologous influenza virus challenge, and generates antibodies which recognize multiple subtypes of influenza virus. When administered to a host, such an immunogen is expected to induce broadly cross-neutralizing antibodies that will protect against challenge with multiple subtypes of influenza A virus. To test this hypothesis, we propose to incorporate the modified HA proteins into vaccine vectors, and to perform vaccine challenge experiments in the mouse model. Furthermore, we plan to characterize the immune response that confers protection following vaccination.
Molecular determinants of influenza virus transmission The first influenza pandemic since 1968 occurred in 2009, following the introduction of a swine origin influenza virus of the H1N1 subtype into humans. Although swine influenza viruses, including H1N1 subtype strains, are occasionally detected in humans who have had direct contact with pigs, these are most often isolated events that do not lead to sustained human-to-human spread. An important question therefore arises: what viral factors allow the efficient transmission of the swine-origin, 2009 pandemic strain among humans? Two approaches will address this question. The first focuses on identifying the genetic and molecular determinants of transmission of the swine-origin influenza virus by testing relevant recombinant viruses in the guinea pig model. We will tease out molecular differences that separate poorly transmitting parental swine viruses, potentially transmissible reassortant viruses carrying swine-origin genes, and the highly transmissible 2009 pandemic virus itself. In this way, the importance of the reassortant gene constellation to transmissibility of the pandemic strain will be evaluated, and an initial indication of which viral genes contribute to molecular transmissibility will be obtained. The second aim focuses on the role of host specific adaptations in determining the transmissibility of putative pandemic precursor viruses. Serial passage of reassortant strains in human or swine cell culture systems will be performed to mimic the process of host adaptation; progeny viruses will then be tested for transmissibility in the guinea pig model. In summary, our research will examine putative evolutionary paths which may have led to the 2009 pandemic strain and, in so doing, identify viral gene constellations and polymorphisms which govern transmissibility and therefore dictate the pandemic potential of influenza viruses derived from animal reservoirs.
Pubmed search terms; Steel J AND (influenza OR respiratory syncytial virus)
David Weiss, Ph.D.
Assistant Professor of Infectious Disease
Microbial pathogenesis and host defense/Francisella
Our lab is interested in understanding mechanisms of bacterial pathogenesis and the host’s response to infection.
We are currently focusing on the Gram-negative bacterial pathogen Francisella tularensis. F. tularensis is highly infectious and causes tularemia, a potentially life-threatening disease in humans. Critical to Francisella’s pathogenesis are its ability to replicate within macrophages, the primary niche for replication in vivo, and to subvert the host immune system. Unfortunately, relatively little is known about which genes Francisella uses to modulate host defenses.
In order to identify critical Francisella virulence genes, we recently employed a powerful global in vivo negative selection screen. This approach resulted in the identification of 164 genes that are required for virulence, 44 of which appear to encode novel virulence factors. Study of mutants lacking two of the novel genes we identified revealed that they act to suppress the macrophage cell death response. We previously described that this pathway, dependent on the host inflammasome complex containing the proteins Caspase-1 and ASC, plays an important role in host defense against Francisella infection. This highlights how Francisella attempts to suppress critical host defenses, and the molecular tug-of-war that takes place between Francisella and the host during infection.
Future work will elucidate the roles of other novel Francisella virulence factors as well as identifying the host defense pathways that they modulate. One area of focus will be determining if and how Francisella subverts dendritic cell function to evade the immune response. Our work will allow us to gain insights into Francisella pathogenesis and host-pathogen interactions, while leading us towards an F. tularensis vaccine and the identification of critical targets for therapeutics to treat tularemia.
Elizabeth Wright, Ph.D.
Assistant Professor of Pediatrics, Division of Infectious Diseases
Cryo-electron microscopy of bacterial and viral pathogens.
The Wright Laboratory employs state-of-the-art cryo-electron microscopy (cryo-EM) to examine host-pathogen ineteractions using both eukaryotic and prokaryotic viruses as model systems to answer questions regarding initial contact, irreversible attachment, assembly, and egress in order to develop novel structure-specific vaccines and therapeutics. Projects include cryo-electron tomography (cryo-ET) of isolated whole cells and viruses, cryo-ET of virus cells, the development of cryo-EM technologies and correlative microscopy methods, and the improvement and application of image processing algorithms to cryo-EM data.
HIV-1: Cryo-EM/cryo-ET has substantially increased our understanding of the basic structure of and the proteolytic maturation of HIV-1. We believe that a major factor limiting the development of HIV-1 therapeutics is our incomplete understanding of structural aspects of the HIV-1 viral life cycle, including: Env-mediated fusion, viral assembly and trafficking, and viral maturation. In collaboration with Professor Paul Spearman (Emory University Division of Pediatrric Diseases), we are probing the morphology and structure-function relationships that exist in the isolated virus and between the virus and cells in order to provide a basis for further biochemical, structural, and vaccine development studies.
Paramyxoviruses (Measles virus): In collaboration with Professor Richard K. Plemper (Emory University Division of Pediatric Infectious Diseases), measles virus (MV) is being studied as a model system for understanding glycoprotein mediated viral fusion. This project addresses two basic questions: What is the spatial organization of paramyxovirus glycoprotein hetero-oligomer complexes in the native, metastable prefusion conformation? How does receptor binding affect this organization? We use cryo-ET and advanced computational approaches to investigate the structure of the glycoproteins of purified MV particles.
Bacteriophages: We aim to understand the mechanistic aspects of the virus life cycle and its effect on the host cell’s steady state in a simple model system. Despite their major importance, the mechanisms involved in the fusion, transfer of genomic material, and assembly of viruses are poorly understood in many biological systems. Our aim is to determine how phage adsorption and attachment is regulated and identify the phage and host factors that control assembly within the cellular host. To achieve these objectives, we use Caulobacter crescentus and its associated phages – a well-established, genetically tractable model system for developmental studies – which is amenable to structural studies at the light microscopy and cryo-EM levels.
Technology Development: In addition to the biological projects, we are developing technologies and methods to push the limits of cryo-EM and its correlation with other imaging modalities.
- We are the first lab in the United States to have a 200 kV FEG-TEM specifically designed and engineered for Zernike phase contrast TEM. This technology provides a significant advantage for higher resolution cryo-EM/cryo-ET imaging of low contrast biological specimens, especially isolated macromolecules, viruses, and bacteria.
- We are developing novel equipment and molecular biology approaches for bridging the information gap between cryo-EM and fluorescence microscopy. This includes the design, manufacture, and use of cryo-stages for confocal microscopy. By rapidly freezing cells cultured on EM grids, we are able to directly correlate fluorescence microscopy images to images collected in the electron microscope. This technology is being applied to fundamental questions about the assembly and trafficking of viruses, like HIV-1, within host cells.