Marcelo B Sztein
Medicine, Microbiology and Immunology
Dr. Sztein received an M.D. degree from the School of Medicine, University of Buenos Aires, Argentina, in 1976. He did his post-doctoral fellowship at NIH with Dr. Joe Oppenheim before becoming a faculty member, first at George Washington University and then at the University of Maryland.
Dr. Sztein joined the Center for Vaccine Development (CVD) in 1989 as Chief of the Cellular Immunology and Flow Cytometry Section. Under Dr. Sztein's leadership, the Immunology Group at the CVD, which he leads, has expanded dramatically. The CVD's Immunology Group currently consists of over 20 individuals, including faculty, laboratory supervisors and other technical personnel, post-doctoral fellows and students.
Dr. Sztein is an accomplished investigator in the area of immunology of infectious diseases. As author and/or co-author of 172 peer-reviewed scientific articles and 36 chapters, meeting reports and monographs, Dr. Sztein is a recognized authority in the human host systemic and mucosal immune response to vaccination and the identification of immunological mechanisms of protection from infection in human and animal models, particularly in the field of infectious enteric diseases (e.g., those caused by S. Typhi S. Paratyphi A and B, Shigella, E. coli). Other areas of interest include studies of humoral, cell-mediated (CMI) and innate immunity in volunteers and animals exposed to wild-type organisms or immunized with candidate vaccines against malaria, influenza, tularemia and hepatitis.
Dr. Sztein has a consistent record of grant support from the NIH, industry and other agencies since 1983 and regularly serves as ad-hoc member or chair in Grant Review Panels of the National Institutes of Health and other organizations. He has recently completed a 4-year term as Standing Member of the Microbiology and Infectious Diseases Research Committee (MIDRC), Microbiology, Infectious Diseases and AIDS Initial Review Group, National Institute of Allergy and Infectious Diseases, NIH (the study section responsible for reviewing K08, K22, K23, K24, K25, K99/R00, T32 and T35 applications). Moreover, he holds membership in numerous scientific societies, is actively involved in the organization of the National/International meetings and serves as reviewer in major peer-reviewed research journals.
Dr. Sztein has an extensive record of training successful scientists. Throughout his career he has mentored numerous students, fellows, and junior faculty. Virtually all of the post-doctoral trainees and fellows which he has mentored over the past 15 years continue to be involved in biomedical sciences in various capacities, including as faculty in US academic institutions, and CDC, FDA, the Naval Medical Research Center and industry. Most have secured career development awards and were the recipients of research grants from NIH and other funding agencies.
Basic and translational models of infectious diseases, chiefly in the areas of vaccine development and host-pathogen interactions, are used in Dr. Sztein's laboratory to uncover the mechanisms underlying protective innate, cellular and antibody immune responses in volunteers and animals.
Current projects encompass studies to investigate systemic and mucosal innate and adaptive immune responses in volunteers participating in vaccine trials being conducted at the CVD and other sites, including underdeveloped countries. These trials involve the clinical testing of genetically engineered attenuated vaccine strains developed at the CVD and other institutions, such as attenuated S. Typhi and Shigella (alone or as carriers of foreign genes). Of particular importance, in collaboration with Dr. Pollard -Oxford, UK- and others, Dr. Sztein is performing in depth immunological studies using specimens from subjects orally challenged with wild-type S. Typhi, as well as subjects vaccinated with attenuated typhoid vaccine candidates followed by a challenge with wt S. Typhi.
Dr. Sztein is the principal investigator in an NIH Research Project Cooperative Agreement (U19) entitled "Mucosal Immunity, Vaccines and Microbiota Interplay in Humans and Animal Models", one the Cooperative Centers for Translational Research on Human Immunology and Biodefense (CCHI) NIAID network. The UMB CCHI research focuses on furthering our understanding of the protective immunological mechanisms that are elicited upon oral immunization in the gastrointestinal tract microenvironment. Moreover, the CCHI multidisciplinary team of investigators conducts pioneering studies on the interactions between the local intestinal microbiota and the host immunity following oral vaccination, as well as the development of novel technologies to advance and accelerate vaccine development in humans.
Immunological studies in other infectious diseases, including malaria, hepatitis B, influenza and tularemia, are also being performed by Dr. Sztein's team in immunized or naturally exposed subjects and in animal models. These investigations involve microorganisms relevant to bio-defense. The broad goal of these studies is to uncover the immune mechanisms of protection against infectious agents with the long-term goal of accelerating the development of effective vaccines.
Dr. Sztein's group has also been involved for over 2 decades in studies directed to unveil the mechanisms that might underlie the immunosuppression observed in patients with various infectious diseases and the mechanisms underlying decreased immunity to vaccination in elderly volunteers.
Finally, Dr. Sztein has participated for many years in international collaborative studies and is deeply committed to the training of investigators in underdeveloped nations. In this context, he has directed the establishment of a state-of-the-art immunology laboratory (that includes flow cytometry capabilities) at the University of Mali, Bamako and an immunology lab at the Bandiagara field site in Mali, West Africa, to study the immune responses of volunteers in malaria endemic areas.
Lab Techniques and Equipment:
State-of-the-art technologies (e.g., multichromatic flow cytometric analysis and sorting, ELISPOT, DNA microarrays, deep proteomics) are being used in Dr. Sztein's laboratories to study immune responses in animal models and humans, including cytokine production and receptor expression, biochemical pathways of lymphocyte activation, protein phosphorylation, lymphoproliferative responses, cytotoxic T cell activity, B memory responses, antibody secreting cell levels and their homing potential.
Advanced flow cytometry instrumentation includes
(i) a Beckman-Coulter MoFlo Flow cytometer/cell sorter system equipped with three lasers, 10 ultra-high sensitivity PMTs plus an additional side scatter PMT and a forward scatter diode to collect light scatter parameters, a 4-Way sorting system which allows the simultaneous collection of 4 sorted populations, SortMaster and SortRescue Modules , an Ultra-high Speed Sorting Module, a Cyclone automated cell deposition unit allowing for the cloning of individual cells by depositing them into individual wells of multi-well tissue culture plates and an Aerosol Management Option (AMO).
(ii) A custom Becton-Dickinson LSR-II Flow cytometer analyzer equipped with four lasers and 17 ultra-high sensitivity PMTs (e.g., capable of collecting 15/16 colors simultaneously) plus forward and side light scatter parameters, and
(iii) A recently installed CyTOF Mass Cytometer. The DVS Sciences CyTOF Mass Cytometer is a revolutionary single-cell analyzer which uses mass spectrometry to allow the simultaneous detection of at least 35 metal-labeled antibodies and two DNA intercalators - one for cell identification and one for live/dead discrimination in a single panel. Unlike traditional flow cytometers, there is no overlap of the emission signals, which means there is no need for compensation and there is no background above the instrument noise. The CyTOF in our facility is equipped with an Autosampler, which can handle up to three 96-well plates.
CVD Cellular Immunology Section & Flow Cytometry Core Laboratory
- Rosangela Mezghanni, Ph.D. Assistant Professor
- M. Rezwanul Wahid, M.D., Ph.D. Assistant Professor
- Franklin Toapanta, M.D., Ph.D., Research Associate
- Monica McArthur, M.D., Ph.D., Research Fellow
- Stephanie Fresnay, Ph.D., Post-doctoral fellow
- Jayaum Booth, Ph.D., Post-doctoral fellow
- Regina Harley, M.S. Research Specialist
- Catherine Storrer, B.S. Research Specialist
- Haiyan Chen, M.D., Research Specialist
- Jeffrey Floyd, B.S., Research Assistant
- Paula Bernal, Ph.D.
- David Luo, Student
Positions are available for postdoctoral fellows and graduate students wishing to join a multidisciplinary group that focuses on basic and translational studies in several models of infectious diseases directed to uncover the mechanisms underlying protective innate, cellular and antibody immune responses to a variety of microorganisms in volunteers and animals, chiefly in the areas of vaccine development and host-pathogen interactions.
Studies include working with specimens obtained from adults and elderly subjects immunized with genetically engineered strains of Salmonella enterica serovar Typhi and Shigella vaccine candidates, as well as immunized with malaria, hepatitis B, influenza and tularemia vaccines. Areas of study include antigen presentation, MHC-restriction, cloning and characterization of cytotoxic and helper T cells, identification of protective epitopes, role of dendritic and regulatory T cells, microarray profiling and manipulation of cytokine production patterns to elucidate their role in the induction of innate, systemic and mucosal immune responses to vaccination and the mechanisms of immunosenescence.
The Center for Vaccine Development (CVD) offers a unique environment to study cellular and molecular determinants of protection to infectious diseases in humans. The CVD, largely supported by NIH funding and private foundations, has earned an international reputation for genetically engineering and testing vaccines against typhoid, shigella, cholera and malaria. Based at the School of Medicine, University of Maryland, Baltimore, the CVD was established in the mid-1970s as one of the first facilities to evaluate vaccines in community volunteers. It is one of only a handful of vaccine centers in the world engaged in the full range of vaccinology - from basic science through vaccine development, immunological studies, clinical evaluation and field studies. Contact Dr. Marcelo Sztein for additional information.
Publications in peer-reviewed journals (since 2009, from a total of 172)
- Simon, J.K., Wahid, R., Maciel Jr., M., Picking, W.L., Kotloff, K.L., Levine, M.M. and Sztein, M.B. Antigen-specific B memory cell responses to lipopolysaccharide (LPS) and invasion plasmid antigen (Ipa) B elicited in volunteers vaccinated with live-attenuated Shigella flexneri 2a vaccine candidates. Vaccine 27: 565-572, 2009. PMID: 19022324
- Ramirez, K., Capozzo, A.V.E., Lloyd, S.A., Sztein, M.B., Nataro, J.P. and Pasetti, M.F. Mucosally delivered Salmonella Typhi expressing the Yersinia pestis F1 antigen elicits mucosal and systemic immunity early in life and primes the neonatal immune system for a vigorous anamnestic response to parenteral F1 boost. J. Immunol. 182: 1211-1222, 2009. PMID: 19124765
- Lyke, K.E., Daou, M., Diarra, I., Kone, A. Kouriba, B., Thera, M.A., Heppner, D.G., Doumbo, O.K., Plowe, C.V. and Sztein, M.B. Cell Mediated Immunity Elicited by the Blood Stage Malaria Vaccine Apical Membrane Antigen 1 in Malian Adults: Results of a Phase I Randomized Trial. Vaccine. 27: 2171-2176, 2009. PMID: 19356621. PMC2707027.
- Galen, J.E., Pasetti, M.F., Tennant, S., Ruiz-Olvera, P., Sztein, M.B., Levine, M.M. Salmonella enterica serovar Typhi Live Vector Vaccines Finally Come of Age. Immunology and Cell Biology. 87: 400-412, 2009. PMID: 19417771
- Chen, W.H., Kozlovsky, B.F., Effros, R.B., Grubeck-Loebenstein, B., Edelman, R. and Sztein, M.B. Vaccination in the elderly: an immunological perspective. Trends in Immunology 30: 351-359, 2009. PMID: 19540808
- Salerno-Gonçalves, R. and Sztein, M.B. Priming of Salmonella enterica serovar Typhi-specific CD8+ T cells by suicide dendritic cell cross-presentation in humans. PLoS ONE 4: e5879, 2009. PMID: 19517022
- El Sahly, H.M., Atmar, R.L., Patel, S.M., Wells, J.M., Cate, T., Ho, M., Guo, K., Pasetti, M.F., Lewis, D.E., Sztein, M.B. and Keitel, W.A. Safety, Reactogenicity and Immunogenicity of Francisella tularensis Live Vaccine Strain in Humans. Vaccine 27: 4905-4911, 2009. PMID: 19567246.
- Salerno-Gonçalves, R., Hepburn, M.J., Bavari, S. and Sztein, M.B. Generation of heterogeneous effector and memory T cells by live attenuated tularemia vaccine in humans. Vaccine. 28: 195-206, 2009. PMID: 19799845.
- Shipley, S.T., Panda, A., Khan, A.Q., Kriel, E.H., Maciel, M., Livio, S., Nataro, J.P., Levine, M.M., Sztein, M.B. and DeTolla, L.J. A challenge model for Shigella dysenteriae 1 in cynomolgus macaques. Comparative Medicine. 60: 54-61, 2010. PMID: 20158950
- Salerno-Gonçalves, R., Wahid, R. and Sztein, M.B. Ex vivo Kinetics of Early and Long-Term Multifunctional HLA-E specific CD8+ Cells in Volunteers Immunized with the Ty21a Typhoid Vaccine. Clinical Vaccine Immunology. 17: 1305-1314, 2010. PMID: 20660136.
- El-Kamary, S.S., Pasetti, M.F., Mendelman, P.M., Frey, S.E., Bernstein, D.I., Treanor, J.J., Ferreira, J., Chen, W.H., Sublett, R., Richardson, C, Robert F. Bargatze, R.F., Sztein, M.B. and Tacket, C.O. Adjuvanted Intranasal Norwalk VLP Vaccine Elicits Antibodies and Antibody Secreting Cells Expressing Homing Receptors in Mucosal and Peripheral Lymphoid Tissues. J. Infectious Diseases. 202: 1649-1658, 2010. PMID: 20979455.
- Pasetti, M.F., Simon, J.K., Sztein, M.B. and Levine, M.M. Immunology of Gut Mucosal Vaccines. Immunological Reviews. 239: 125-148, 2011. PMID: 21198669.
- Wahid, R., Pasetti, M.F., Maciel, Jr. M., Simon, J.K., Tacket, C.O., Levine, M.M. and Sztein, M.B. Oral priming with Salmonella Typhi vaccine strain CVD 909 followed by parenteral boost with the S. Typhi Vi capsular polysaccharide vaccine induces CD27+ IgD- S. Typhi specific IgA and IgG B memory cells in humans. Clin. Immunol. 138:187-200, 2011. PMID: 21146460.
- Simon, J.K., Maciel Jr., M., Weld, E.D., Wahid, R., Pasetti, M.F., Picking, W.L., Kotloff, K.L., Levine, M.M. and Sztein, M.B. Antigen-specific IgA B memory cell responses to Shigella antigens elicited in volunteers immunized with live attenuated Shigella flexneri 2a oral vaccine candidates. Clin. Immunol. 139:185-192, 2011. PMID: 21388888.
- Chen, W.H., Cross, A.S., Edelman, R. Sztein, M.B., Blackwelder, W.C. and Pasetti, M.F. Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose- influenza vaccine. Vaccine. 29: 2865-2873, 2011. PMID: 21352939.
- Gunther, V.J., Putnak, R., Eckels, K.H., Mammen, M.P., Scherer, J.M., Lyons, A., Sztein, M.B. and Sun, W. A Human Challenge Model for Dengue Infection Reveals a Possible Protective Role for Sustained Interferon Gamma Levels During the Acute Phase of Illness. Vaccine. 29: 3895-3904, 2011. PMID: 21443963.
- Lyke, K.L., Fernández-Viňa, M.A., Cao, K., Hollenbach, J., Coulibaly, D., Kone, A.K., Guindo, A., Burdett, L.A., Hartzman, R.J., Wahl, A.R., Hildebrand, W.H., Doumbo, O.K., Plowe, C.V. and Sztein, M.B. Association of HLA alleles with Plasmodium falciparum severity in Malian children. Tissue Antigens. 77: 562-571, 2011. PMID: 21447146. PMC3152196.
- Ulmer, J.B. and Sztein, M.B. Promising Cutting-edge Technologies and Tools to Accelerate the Discovery and Development of New Vaccines. Editorial overview. Current Opinion in Immunology. 23: 1-3, 2011. PMID: 21524899. NIHMSID #367382.
- 19. Salerno-Goncalves, R., Fasano, A. and Sztein, M.B. Engineering of a multicellular organotypic model of human intestinal mucosa. Gastroenterology. 141:e18-21, 2011. PMID: 21723866. NIHMSID # 367376
- Ruiz-Perez, F. Wahid, R., Faherty, C.S., Kolappaswamy, K., Rodriguez, L., Santiago, A., Murphy, E., Cross, A., Sztein, M.B., Nataro, J.P. Serine protease autotransporters from Shigella flexneri and pathogenic Escherichia coli target a broad range of leukocyte glycoproteins. PNAS. 108: 12881-12886, 2011. PMID: 21768350. PMCID: PMC3150873
- Simon, J.K., Carter, M., Pasetti, M.F., Sztein, M.B., Kotloff, K.L., Weniger, B.G., Campbell, J.D., Levine, M.M. Safety, Tolerability, and Immunogenicity of Inactivated trivalent seasonal influenza Vaccine administered with a needle-free disposable-syringe jet injector. Vaccine. 29: 9544-9550, 2011. PMID: 21986218.
- Lyke, K.L., Dabo, A., Arama, C., Daou, M., Diarra, I., Wang, A., Plowe, C.V., Doumbo, O.K. and Sztein, M.B. Reduced T Regulatory Cell Response during Acute Plasmodium falciparum Infection in Malian Children Co-infected with Schistosoma haematobium. PLoS One. 7: e31647, 2012. PMID: 22348117. PMC3279404.
- Fernández-Viňa, M.A., Hollenbach, J.A., Lyke, K.E., Sztein, M.B., Maiers, M., Klitz, W., Cano, P., Mack, S., Single, R., Brautbar, C., Israel, S., Raimondi, E., Khoriaty, E., Inati, A., Andreani, M., Testi, M., Moraes, M.E., Thomson, G., Stastny, P., Cao, K. Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations. Phil Trans R Soc B. 367: 820-829, 2012. PMID:22312049
- Wahid, R., Simon, R., Zafar, S.J., Levine, M.M., Sztein, M.B. Live oral typhoid vaccine Ty21a induces cross reactive humoral immune responses against S. Paratyphi A and S. Paratyphi B in humans. Clinical and Vaccine Immunology. 19: 825-834, 2012. PMID: 22492745.
- Lyke, K.L., Wang, A., Dabo, A., Arama, C., Daou, M., Diarra, I., Plowe, C.V., Doumbo, O.K., Sztein, M.B. Antigen-Specific B Memory Cell Responses to Plasmodium falciparum Malaria Antigens and Schistosoma haematobium Antigens in Co-infected Malian Children. PLoS One. 7: e37868, 2012. PMID: 22693628. PMC3367916.
- McArthur, M.A. and Sztein, M.B. Heterogeneity of multifunctional IL-17A producing S. Typhi-specific CD8+ T cells in volunteers following Ty21a typhoid immunization. PLoS One. 7: e38408, 2012. PMID: 22679502.
- Ramirez, K., Wahid, R., Richardson, C., Bargatze, R.F., El-Kamary, S.S., Sztein, M.B., Pasetti, M.F. Intranasal vaccination with an adjuvanted Norwalk virus-like particle vaccine elicits antigen-specific B memory responses in human adult volunteers. Clin. Immunol. 144: 98-108, 2012. PMID: 22710446.
- Toapanta, F.R., Bernal, P.J., Sztein, M.B. Diverse phosphorylation patterns of B cell receptor-associated signaling in naive and memory human B cells revealed by phosphoflow, a powerful technique to study signaling at the single cell level. Frontiers in Cellular and Infection Microbiology. Frontiers Microbiology. 2: 128, 2012. PMID:23087912.
- McArthur, M.A. and Sztein, M.B. Unexpected heterogeneity of multifunctional T cells in response to superantigen stimulation in humans. Clin. Immunol. 146: 140-152, 2013. PMID 23333555 NIHMSID #436845.
- Fiorentino, M., Ding, H., Blanchard, T.G., Czinn, S.J., Sztein, M.B. and Fasano, A. Helicobacter pylori induced disruption of monolayer permeability and proinflammatory cytokine secretion in polarized human gastric epithelial cells. Infection & Immunity. 81: 876-883, 2013. PMID: 23297384
- Fiorentino, M., Lammers, K.M., Levine, M.M., Sztein, M.B.* and Fasano, A*. In Vitro Intestinal Mucosal Epithelial Responses to wild-type Salmonella Typhi and attenuated Typhoid Vaccines. Frontiers in Mucosal Immunity. Frontiers in Immunology. 4: 17, 2013. *Joint senior authorship
- Barry, E.M., Pasetti, M.F., Sztein, M.B., Fasano, A., Kotloff, K.L., Levine, M.M. Progress and pitfalls in Shigella vaccine research. Nature Reviews Gastroenterology and Hepatology. 10: 245-255, 2013. PMID: 23419287.
- Davis, C.L., Wahid, R., Toapanta, F.R., Simon, J.K., Sztein, M.B.,* Levy, D.* Applying Mathematical Tools to Accelerate Vaccine Development: Modeling Shigella Immune Dynamics. PLoS One. 8:e59465, 2013. *Joint senior authorship
- Wahid, R., Simon, J.K., Picking, W.L., Kotloff, K.L., Levine, M.M., Sztein, M.B. Shigella antigen-specific B memory cells are associated with decreased disease severity in subjects challenged with wild-type Shigella flexneri 2a. Clin. Immunol. 148: 35-43, 2013.
- Eloe-Fadrosh, E.A., McArthur, M.A., Seekatz, A.M., Drabek, E.F., Rasko, D.A., Sztein, M.B.*, Fraser, C.M.* Impact of oral typhoid vaccination on the human gut microbiota and correlations with S. Typhi-specific immunological responses. PLoS One. In press. 2013. *Joint senior authorship.
- Seekatz, A.M., Panda, A., Rasko, D.A., Toapanta, F.R., Eloe-Fadrosh, E.A., Khan, A.Q., Liu, Z., Shipley, S.T., DeTolla, L.J., Sztein, M.B., Fraser, C.M. Differential response of the cynomolgus macaque gut microbiota to Shigella Infection. PLoS One. In press. 2013.