I was introduced to laboratory research as a high school student in my father's chemical engineering/materials science laboratory at the University of New Hampshire. I spent all of my high school and college summers in his laboratory, except for one that I spent as a research intern at the Centre National de Recherche Scientifique in Lyons, France, working on problems in polymer morphology development. This work led to several peer-reviewed journal articles, the first of which was Sundberg & Sundberg, 1993.
My work in the field of structural immunology began as a graduate student at Northwestern University (in the laboratory of Dr. Theodore S. Jardetzky, now at Stanford University) and continued as a postdoctoral fellow at the Center for Advanced Research in Biotechnology-University of Maryland Biotechnology Institute (now the Institute for Bioscience and Biotechnology Research at the University of Maryland College Park; in the laboratory of Dr. Roy A. Mariuzza). Three years after receiving my Ph.D., I became an Assistant Professor at CARB-UMBI, and was awarded an NIH R21 award to support my independent work on superantigen structure and function and the development of protein therapeutics that act as superantigen antagonists.
I moved to the Boston Biomedical Research Institute (BBRI) in 2004 to start an independent research group where the extension of my work on superantigens and drug development was supported by an NIH R01 award. While at BBRI, I expanded my laboratory’s research scope to incorporate studies aimed at understanding the biophysical basis of HIV immune evasion and innovative HIV vaccine development, which has resulted in additional NIH R01 Awards to investigate the molecular bases of myelomonocytic MHC class I receptor function in HIV-1 infection and of ADCC-mediated HIV protection. I also assumed several leadership roles while at BBRI, including the leader of the Integrative Protein Biology program and the director of the Protein Structure and Interactions Center.
In April 2011, I moved my laboratory to the Institute of Human Virology and the Department of Medicine at the University of Maryland School of Medicine. I have a secondary appointment in the Department of Microbiology and Immunology.
Additionally, I am a member of the following GPILS Ph.D. programs: Molecular Microbiology & Immunology; Molecular Medicine; and Biochemistry & Molecular Biology. Graduate students in these programs are encouraged to explore their research interests in my lab during research rotations and, potentially, to join my lab afterward to conduct research for their thesis projects.
The main research interests of my research program lie in defining molecular mechanisms of infection and immunity at atomic resolution and developing novel protein- and peptide-based therapeutics to treat a range of infectious diseases. Our studies aim to better understand ways in which microbes colonize and interact with the host to replicate themselves and to cause diseases such as immunodeficiency, cancer, shock, asthma, psoriasis and colitis. We also seek to define the innate and adaptive immune responses to a variety of pathogens and to manipulate the immune response as a means to create novel therapeutics.
Nearly all cellular processes, including those involved in infection and immunity, depend critically on protein-protein interactions. Many human diseases are a result of proteins from microbes interacting with host proteins, or mutations in human proteins, that dysregulate signaling pathways. Research in my laboratory focuses on understanding protein-protein interactions, both to define the molecular basis of and to develop novel therapeutics against particular diseases, as well as to define the fundamental driving forces that govern specificity and affinity in protein-protein interactions more generally. To do so, we combine the tools of protein engineering (e.g., directed evolution) with those in structural biology (e.g., X-ray crystallography and nuclear magnetic resonance) and molecular biophysics (e.g., surface plasmon resonance and isothermal titration calorimetry).
Current projects in my laboratory include:
Viral Infections – HIV/AIDS
My research group currently conducts several HIV-related projects. The first of two projects related to characterizing natural immunity to HIV exhibited by some individuals is an investigation of the molecular basis of antibody-dependent cellular cytotoxicity in elite controller or natural virus suppressor populations versus individuals with progressive disease. The second project concerning natural immunity to HIV is aimed at understanding the role of single-nucleotide polymorphisms in the human leukocyte antigen locus that strongly correlated with natural HIV control. These studies could lead to the development of novel HIV/AIDS vaccines in pre-exposed populations or adaptive T cell therapies in HIV-infected individuals. Our third HIV-related project focuses on determining the molecular basis of myelomonocytic receptor interactions with cytotoxic T lymphocyte escape variants of HIV antigens displayed by MHC class I molecules, a novel immune escape mechanism utilized by HIV. Again, these studies are poised to lead to novel protein-based therapeutics against HIV infection.
Bacterial Oncology – Helicobacter Pylori-Induced Gastric Cancer
A protein virulence factor from Helicobacter pylori, CagA, causes gastric adenocarcinoma through its ability to alter cell signaling pathways in human gastric epithelial cells. CagA is a polymorphic protein, and the genetic differences between distinct strains of H. pylori correlate with the risk of developing cancer. The molecular basis of how CagA polymorphisms result in differential interactions with host cell proteins, subsequent changes in cell signaling, and the development of gastric cancer is poorly understood. We are currently working towards determining the X-ray crystal structure of CagA in complex with its molecular chaperone, CagF. We are also defining the stoichiometric, kinetic and thermodynamic parameters of CagA/CagF binding. We are extending these studies to investigate the molecular basis of CagA complex formation with human host cell proteins known to be important in the dysregulation of cellular signaling associated with gastric cancer, including apoptosis-stimulating of p53 protein 2 (ASPP2).
Bacterial colonization and virulence – Type IV pilin proteins and assembly
Clostridium difficile, a spore-forming anaerobic Gram positive bacillus, is the cause of a spectrum of gastrointestinal illnesses, the incidence, severity and mortality of which have all increased significantly in the past twenty years. The mechanism of C. difficile toxicity is well-characterized but no vaccine against C. difficile infection exists and our knowledge concerning the interactions of C. difficile with its host is limited. Type IV Pili (T4P) are hair-like surface appendages produced by many species of pathogenic Gram negative bacteria which play a role in diverse processes such as cellular adhesion, colonization, twitching motility, biofilm formation, horizontal gene transfer and in numerous instances are essential for virulence. T4Ps are composed exclusively or primarily of many copies of pilin protein, tightly packed in a helix so that the highly hydrophobic amino-terminus of the pilin is buried in the pilus core. Recently, T4P genes have been discovered in the genomes of all members of the genus Clostridium including C. difficile. The genomes of C. difficile strains sequenced to date all have a single gene cluster encoding a complete set of T4P biogenesis components, a second cluster with three genes, and a variable number of additional pilin genes. We are determining the structural bases of their roles in colonization and virulence, including the mechanisms by which they assemble and their interactions with the host.
Bacterial Infections – Toxic shock
Since its inception, my laboratory has been studying the molecular basis of toxic shock syndrome and other human diseases caused by the overstimulation of the immune system by a family of bacterial protein toxins, superantigens, secreted predominantly by Staphylococcus aureus and Streptococcus pyogenes. We continue our studies to fully define the molecular basis of T cell activation by superantigens, as well as the engineering of T cell receptor-based protein therapeutics against superantigen-related disease, which we have shown to be completely protective against a particular superantigen in animal models of superantigen-mediated lethality.
Innate Immune Responses – Toll-like receptor signaling
Toll-like receptors (TLRs) recognize conserved microbial molecules such as lipopolysaccharides (LPS), lipopeptides, dsDNA, ssRNA, and flagellin to induce “innate” immune responses to infection. TLRs can also be activated by endogenous ligands associated with tissue damage of various etiologies. Although genetic deficiencies in TLR pathway components often result in increased susceptibility to infection, excessive TLR responses can be detrimental, even lethal, to the host when they lead to unregulated inflammation. Each TLR is composed of an extracellular domain connected, by a transmembrane region, to a cytoplasmic Toll/Interleukin-1 Receptor Resistance (TIR) protein domain. Ligand engagement by TLR ectodomains leads to dimerization and/or structural rearrangement of receptor TIR domains, followed by recruitment of adapter proteins, each of which also contains a TIR domain, to trigger inflammatory signaling pathways. As interactions between TIR domains of TLR and adapter proteins are absolutely required for TLR signaling, specific inhibition of the TIR-mediated assembly of these cytoplasmic protein complexes is a viable and attractive strategy for treating a broad spectrum of diseases with an inflammatory component, including infectious diseases caused by priority pathogens. We are using protein engineering combined with structural biology to determine the molecular basis for TLR signaling mediated by TIR domain interactions.
Innate Immune Responses – Interleukin signaling
Cytokines of the IL-1 family are potent activators of the innate immune response that also shape the adaptive immune response by driving TH cell responses through enhancing T cell lineage commitment. For example, IL-1β has been shown to enhance TH17 type responses, whereas IL-18 mediates TH1 and IL-33 drives TH2 responses. IL-1 family-mediated signaling occurs in several steps starting with the binding of the interleukin to its cognate receptor. Upon sequestering a second receptor, the receptor accessory protein (IL-RAcP), a signaling cascade is initiated that results in enhanced inflammatory gene activation and cytokine release. The IL-1 family consists of 11 known interleukins that can be grouped according to their primary receptor. The IL-1 receptor (IL-1R) binds IL-1a and IL-1b, which are both agonists, and IL-1 receptor antagonist (IL-1Ra). IL-18R binds IL-18 (agonist) and IL-37 (antagonist). ST2 binds to IL-33, an agonist, but there is no known antagonist interleukin that binds specifically to ST2. IL-36R binds to IL-36a, IL-36b and IL-36g (all three agonists), as well as IL-36Ra and IL-38 (both antagonists). Furthermore, there exist two distinct receptor accessory proteins – IL-18R exclusively uses IL-18RAcP whereas the other three receptors, IL-1R, ST2 and IL-36R, all share IL-1RAcP as a secondary receptor. We are defining the molecular mechanisms of agonism and antagonism of signaling through ST2 and IL-36R, and engineering novel “super-antagonists” of these signaling pathways to be used as asthma (ST2) and psoriasis (IL-36R) therapeutics.
Dissecting Protein - Protein Interactions Using Directed Evolution
Due to the importance of protein-protein interactions in nearly all aspects of biology, efforts to decipher the rules that govern these associations have been underway for decades. In order to better quantify the various effects that contribute to protein molecular recognition, model protein-protein interaction systems are often generated that can be perturbed in a controllable manner to alter one factor that affects binding in isolation, and subsequently assessed for structural and energetic changes resulting from that perturbation. Altering these model systems is commonly achieved by mutating individual amino acid residues and measuring the effects of each individual mutation. However, many properties of proteins that affect binding are not restricted to the effects of a single amino acid residue but instead are dependent on the coordinated behavior of numerous residues within an interface. Indeed, there exists a significant degree of networked communication between interface residues that serves as a significant energetic driver for interaction. To address this key issue in protein molecular recognition, we have pioneered the use of directed evolution to develop model protein-protein interaction systems from which the networked energetics within protein interfaces can be quantified. We are currently defining the roles of energetic cooperativity and of disordered protein regions in protein complex formation.
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