Marzena Pazgier

PhD

  • Professor with tenure, Infectious Diseases Division, Department of Medicine of School of Medicine, Medicine
  • Professor with tenure, Basic Sciences

Accepting PhD Students

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20012024

Research activity per year

Personal profile

Research interests

Dr. Pazgier is a Professor in the Infectious Disease Division of the Department of Medicine. She holds additional appointments in the Department of Biochemistry and Molecular Biology and the Emerging Infectious Disease and Molecular Cell Biology Graduate Programs of USU.  Prior to joining USU, Dr. Pazgier was a faculty member of the Institute of Human Virology in the School of Medicine at the University of Maryland, Baltimore, MD. She is a graduate of Lodz University of Technology, Poland in technical sciences and did her postdoctoral training in the structural biology of infectious disease at the Molecular Crystallography Laboratory in the National Cancer Institute, NIH at Frederick, MD.

Dr. Pazgier's research focuses on understanding mechanisms of molecular recognition in human disease with the goal to translate that knowledge into medical applications. This primarily takes the form of directing a substantial, extramurally funded research program in which her group applies structural biology by X-Ray crystallography and single particle cryo-EM, structure-function analysis and other biochemical and biophysical tools to elucidate the molecular basis of the mechanisms involved in disease and in host innate and adaptive responses with the ultimate goal of generating basic knowledge and developing new vaccines, small compounds or antibody/protein therapeutics. Dr. Pazgier's program is currently focused on three major areas that include antimicrobial action of defensins, HIV-1, and most recently SARS-CoV-2.

Antibody effector functions to HIV-1 and new vaccine candidates: Dr. Pazgier group aims to understand the molecular basis of mechanisms governing broad and potent antibody-dependent cellular cytotoxicity (ADCC) of antibodies against HIV-1. ADCC is a mechanism whereby antigen-antibody complexes on an HIV-1 infected cell arm effector cells enabling them to lyse the target. Thus, ADCC is a major mechanism of Ab-mediated protection against HIV-1, yet little is known about the optimal configuration of antigen-antibody complexes that elicit potent cell lysis. Dr. Pazgier’s group is attacking this problem by defining structures of potent and less potent antigen-antibody complexes at the atomic level to define the common structural features of the potent epitope targets so that they can be engineered into new vaccines against HIV-1. Resulting from this research are the first molecular models of how epitope structure and the mode of antibody attachment can dramatically affect ADCC potency and the development of a new immunogen, referred to as ID2, which specifically induces an ADCC response to HIV-1 in laboratory animals (PCT/US2015/045940) and is a candidate for future challenge studies.  

New strategies for a HIV-1 functional cure through ADCC: In HIV-1 infection, many antibodies are elicited to Envelope (Env) epitopes that are conformationally masked in the native trimer and are only available for antibody recognition after the trimer binds host cell CD4. Among these are epitopes within the Co-Receptor Binding Site (CoRBS) and the constant regions 1 and 2 (C1-C2 or Cluster A region). In particular, C1-C2 epitopes map to the gp120 face interacting with gp41 in the native, ‘closed’ Env trimer present on HIV-1 virions or expressed on HIV-1 infected cells. Antibodies targeting this region are therefore non-neutralizing and their potential as mediators of ADCC of HIV-1 infected cells is diminished by a lack of available binding targets. Dr. Pazgier’s group aims to describe conformations of HIV-1 Env on infected cell surfaces and to develop various intervention strategies to eliminate HIV-1 infected cells through ADCC alone or by combining ADCC with neutralization of the virus. Recent effort in this team includes a new antibody based therapeutic capable of sensitizing HIV-1 virions and HIV-1-infected cells in ART-treated individuals by mechanisms that involve both direct virus neutralization and ADCC (patent application number 63/209,192) and a set of small molecule compound inhibitors that bind within the CD4-binidg cavity of the HIV-1 envelope to block viral binding to the host cell.

Pan-neutralization of HIV-1 and HIV-1 inhibition by small compound CD4 mimetic inhibitors: The first step in the HIV-1 entry process is the attachment of the Env trimer to target cell CD4.  As such, the CD4 binding site (CD4bs) remains one of the few universally accessible sites on the Env trimer.  Few antibodies are able to capitalize on this however, due the steric constraints involved in accessing the CD4bs.  We recently characterized a near pan neutralizing antbody lineage, referred to as the N49P series, isolated from the plasma of an HIV-1 “elite neutralizer” which utilizes unique interactions to the highly conserved gp120 inner domain to achieve its remarkable neutralization breadth and potency. The details of interaction of this Ab class with Env antigens pave the way for the creation of the next generation of HIV-1 neutralizing Antibodies to be used in preformed vaccines and HIV-1 therapeutics. Based on their understanding of the interaction of CD4 and CD4 binding site specific antibodies with HIV-1 Env Dr. Pazgier’s group has been involved in development of a series of small compound inhibitors that mimic CD4 within the Env CD4 binding cavity, specifically inhibit viral entry and help inactivate HIV-1 infected cells through the ADCC mechanism.

Fc-effector antiviral mechanism in Non-human Primates (NHPs): Despite evolutionary proximity, there are significant immunological differences between humans and the Old World monkeys, Rhesus macaque (RM), the most frequently used primate model organism to study human disease. Dr. Pazgier’s program aims to fill the existing gap in understanding the molecular basis of the antibody-mediated humoral response in RM and in human. This takes the form of characterizing humoral response components and their interplay at the molecular level, e.g. IgG and IgA antibodies, Fc receptors, C1q complement, etc. in human and RM, to define similarities and differences and to map antibody Fc biology across the species barrier.

Structural basis of the adaptive response to SARS-Cov-2 and new therapeutic interventions: Dr. Pazgier’s group uses structural biology to understand the molecular basis of anti-SARS-CoV-2 antibody interactions with their primarily viral targets that lead to broad and potent neutralization and ADCC. The ultimate goal of these studies is to enable the development of new vaccine candidates, design new antibody-based therapeutics and investigate other intervention strategies for SARS-CoV-2 treatment. Recent results from this team includes characterization at a molecular level of a series of broad and potent neutralizing and ADCC potent antibodies isolated from infected individuals and the development of angiotensin-converting enzyme 2 (ACE2) into an immunoglobulin/immunoadhesin with broad antiviral activity against SARS-CoV-2, Variants of Concern (VOCs) and other emerging ACE2-dependent beta-coronaviruses.

Human defensins: Defensins are small cationic and cysteine-rich peptides that belong to the group of antimicrobial peptides. In vivo, defensins kill bacteria, fungi, and viruses through mechanisms involving mainly electrostatic interactions. Dr Pazgier’s studies provided the first evidence of a role of hydrophobic residues in the action of defensins on bacterial/viral membranes. These studies also revealed a role for oligomerization in defensin function and showed that defensins also target microbe-specific lipid receptors and thus can be used as novel antibiotics targeting opportunistic bacteria or bacterial biofilms.

Education/Academic qualification

Postdoctoral Fellow, National Cancer Institute, NIH, Macromolecular Crystallography Laboratory, Frederick, MD

20022007

Ph.D., Chemical Engineering, Lodz University of Technology, Lodz, Poland

19962001

M. S., Biotechnology and Biochemistry, Lodz University of Technology, Lodz, Poland

19911996

External positions

Professor, Molecular Cell Biology (Quaternary), School of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD

2022 → …

Professor, Biochemistry (Tertiary), School of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD

2022 → …

Professor, Emerging Infectious Diseases (Secondary), School of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD

2022 → …

Associate Professor, Molecular Cell Biology (Quaternary), School of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD

20192022

Associate Professor, Biochemistry (Tertiary), School of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD

20192022

Associate Professor, Emerging Infectious Diseases (Secondary), School of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD

20182022

Associate Professor, Infectious Diseases Division, Department of Medicine of School of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD

20182022

Associate Professor, Department of Biochemistry and Molecular Biology, Institute of Human Virology, UMSOM, Baltimore, MD

20172018

Assistant Professor, Department of Biochemistry and Molecular Biology, Institute of Human Virology, UMSOM, Baltimore, MD

20092017

Keywords

  • Q Science (General)
  • Structural biology of infectious disease, HIV-1 , SARS-Cov2, adaptive, innate response, ADCC, antibody, theraputics

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