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Eric J. Sundberg

Eric J. Sundberg Ph.D.

Academic Title: Professor
Primary Appointment: Medicine
Secondary Appointments: Microbiology and Immunology
Additional Title(s): Co-Director, Basic Science Division, Institute of Human Virology; Co-Director, Structural Biology Shared Service, University of Maryland Greenebaum Cancer Center
Location: Institute of Human Virology, N362
Phone: (410) 706-7468

Personal History:

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, where I am Co-Director of the Basic Science Division. I hold academic appointments in the Department of Medicine (primary) and the Department of Microbiology & Immunology (secondary) at the University of Maryland School of Medicine.

I am a member of the Molecular and Structural Biology Program of the NCI-designated University of Maryland Marlene and Stewart Greenebaum Cancer Center and serve as Co-Director of its Structural Biology Shared Service.

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.

Research Interests:

From Biophysics to Biologics

We use the tools of structural biology, molecular biophysics and protein engineering to define the molecular bases of infectious diseases, develop novel protein- and peptide-based therapeutics, and to better understand protein molecular recognition. Our mission is to make fundamental discoveries in infection and immunity and to translate those findings into new treatments for bacterial and viral infections, chronic inflammatory diseases and cancer. Our primary research interests include: antibody effector functions; innate immune signaling; and bacterial pathogenesis and oncogenesis.

Antibody Effector Functions

We seek to understand how certain bacteria evade the host immune response by modifying the structure of IgG antibodies to defeat functional Fc-Fc gamma receptor interactions. Streptococcus pyogenes secretes an endoglycosidase, EndoS, which specifically cleaves biantennarary complex carbohydrates linked to the IgG Fc domain residue Asn297. The resulting deglycosylated antibodies can no longer bind to Fc gamma receptors and, thus, making them functionally inactive. Having determined the crystal structure of EndoS, we are now focusing on further defining its mechanism of action and to engineer new EndoS variants with unique glycan and protein specificities that could be used as therapeutics to treat autoimmune diseases and in the chemoenzymatic synthesis of homogeneously glycosylated antibodies. In a related project, we are rationally manipulating the IgG Fc domain structure by targeted hyper-glycosylation in order to control the ratio of binding affinities to activating versus inhibitory Fc gamma receptors. These novel Fc variants could improve the efficacies of a wide range of tumor immunotherapy antibodies currently used clinically. Recent representative publications include:

  • Trastoy B, Lomino JV, Pierce BG, Carter LG, Günther S, Giddens JP, Snyder GA, Weiss TM, Weng Z, Wang LX, Sundberg EJ. Crystal structure of Streptococcus pyogenes EndoS, an immunomodulatory bacterial endoglycosidase specific for human IgG antibodies. Proc Natl Acad Sci USA 2014; 111: 6714-6719. PMID: 24753590; PMCID: PMC4020096
  • TrastoyB, Lomino JV, Wang LX, Sundberg EJ. Counter diffusion crystallization improves X-ray diffraction of EndoS, an endo-b-N-acteylglucosaminidase from Streptococcus pyogenes with activity on human IgG. Acta Crystallogr Sect F Struct Biol Cryst Commun 2013; 69:1405-1410. PMCID: PMC3855731

Innate Immune Signaling

The IL-1 family cytokines, inlcuding IL-1, IL-33 and IL-36, control T helper cell differentiation into various T helper cell lineages such as Th1, Th2 and Th17 cells. These cytokines are important messenger molecules for mounting immune responses to infection, but also can lead to chronic inflammatory diseases. For instance, IL-33 drives T cell lineage commitment to Th2 cells and is critically important in the progression and exacerbation of asthma; IL-36 drives T cells to become Th1 cells and is a key pathogenic component of psoriasis. All of these cytokines function in similar ways: they bind their cognate receptors and recruit the common IL-1 receptor accessory protein (IL-1RAcP), bringing together cytoplasmic TIR domains from each that initiates signal transduction. Several mechanisms exist to regulate the activation of these cytokine signaling pathways, including antagonist cytokines that compete for binding to cognate receptors but inhibit IL-1RAcP recruitment, as well as decoy receptors that do not include TIR domains and, thus, cannot signal. We are determining the molecular determinants of agonist and antagonist signaling through ST2 (the IL-33 receptor) and the IL-36 receptor and utilizing this knowledge to engineer super-antagonists and improved decoy receptors of IL-33 and IL-36 signaling. We are also adopting a strategy of designing decoy peptide inhibitors that is highly effective in blocking Toll-like receptor signaling (TLRs also have cytoplasmic TIR domains) to IL-1 family cytokine signaling. Recent representative publications include:

  • Günther S, Sundberg EJ. Molecular determinants of agonist and antagonist signaling through the IL-36 receptor. J Immun 2014; 193:921-930. PMCID in progress.

Bacterial Pathogenesis and Oncogenesis

We have numerous projects investigating bacterial pathogenesis focused on protein appendages and molecular machines found on bacterial cell surfaces, including Type IV pili, Type IV secretion systems and flagella. Type IV pili are fimbrial appendages found on the surfaces of many bacteria and are important for adhesion, colonization, biofilm formation and horizontal gene transfer. They consist of thousands of copies of one or a few pilin proteins arranged in a superhelical formation that can be actively extended and retracted from the bacterial surface. Type IV pili have been extensively studied in Gram-negative bacteria. We have recently solved the first high-resolution structures of Type IV pilin proteins from a Gram-positive bacterium, Clostridium difficile. We are pursuing structures of the additional C. difficile Type IV pilin proteins, determining the supramolecular architecture of the multi-component pilus, and identifying host cell receptors that they engage. We are also investigating another gut microbe, Helicobacter pylori, which is the major causative agent of gastric cancer. H. pylori injects an oncoprotein, CagA, through a Type IV Secretion System into gastric epithelial cells where it carries out numerous biological functions, including the dysregulation of kinase-dependent signal transduction cascades and the apoptotic program, to ultimately cause cellular transformation. We are studying how CagA is delivered through the Type IV Secretion System, how other Cag proteins allow the secretion system to specifically engage host cells and the molecular mechanisms by which CagA dysregulates normal host cell functions. We have recently found that an interaction between the H. pylori adhesin protein HopQ and host cell surface CEACAMs is required for CagA translocation, which has led to our investigations of the structure and function of CEACAMs. Recent representative publications include:

  • Bonsor DA, Günther S, Beadenkopf R, Beckett D, Sundberg EJ. Diverse oligomeric states of CEACAM IgV domains. Proc Natl Acad Sci USA 2015; 112:13561-13566. PMCID: PMC4640789.
  • Bonsor DA, Pham KT, Beadenkopf R, Diederichs K, Haas R, Beckett D, Fischer W, Sundberg EJ. Integrin engagement by a helical RGD motif is regulated by a pH-induced displacement of a neighboring alpha helix. J Biol Chem 2015;290:12929-12940. PMCID: PMC4432307.
  • Piepenbrink KH, Maldarelli GA, Martinez de la Pena CF, Mulvey GL, von Rosenvinge EC, Armstrong GD, Donnenberg MS, Sundberg EJ. Structural and evolutionary analyses show unique stabilization strategies in the Type IV pili of Clostridium difficile. Structure 2015; 23:385-396. PMCID: PMC4318773.
  • Piepenbrink KH, Maldarelli GA, Martinez de la Pena CF, Mulvey GL, Snyder GA, De Masi L, von Rosenvinge EC, Guenther S, Armstrong GD, Donnenberg MS, Sundberg EJ. Structure of Clostridium difficile PilJ exhibits unprecedented divergence from known Type IV pilins. J Biol Chem 2014; 289:4334-4345. PMCID: PMC3924296

Links of Interest:

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