Joseph D. Smith, Ph.D.

As part of Seattle BioMed’s Malaria Program, Joe Smith’s work is focused on the biology of the malaria parasite during the blood stage. The emphasis of his research is to develop blood stage vaccines targeting parasite invasion of erythrocytes and cytoadhesion of infected erythrocytes.

Research

A major area of interest for Smith's lab is to better understand the processes of antigenic variation and cytoadherence of Plasmodium falciparum infected erythrocytes. During blood stage development, P. falciparum parasites export cytoadhesive proteins to the surface of infected erythrocytes and sequester them from blood circulation by binding to blood microvessels. This process allows parasites to avoid spleen-dependent killing mechanisms, but it is involved in the pathogenesis of cerebral malaria and placental malaria.

Infected erythrocyte binding is mediated by a large family of clonally variant proteins, called PfEMP1 proteins, which switch expression to evade host immunity and orchestrate parasite binding tropism. We are interested in understanding PfEMP1 protein trafficking to the erythrocyte surface, how this protein family evolves to evade immunity, and in developing interventions to prevent cytoadhesion-based complications of malaria infections.

Another research focus is to design novel vaccine approaches to elicit invasion blocking antibodies that can prevent parasite invasion of erythrocytes.

Themes

Cytoadherence of infected erythrocytes
Pregnancy malaria
Invasion blocking vaccine approaches

Biography

Education

Ph.D. Immunology Washington University in St. Louis

B.A. Biology Macalester College

Professional Experience

Affiliate Associate Professor, Depts. of Global Health and Pathobiology, University of Washington, 2006-present
Associate Member, Seattle Biomedical Research Institute, 2006-present
Assistant Member, Seattle Biomedical Research Institute, 2002-2006
Faculty Member, Cell and Molecular Biology Program, Colorado State University, 2000-2002
Assistant Professor, Colorado State University, 1999-present
Postdoctoral Research Fellow with Dr. Louis Miller, Laboratory of Parasitic Diseases, NIAID, NIH, 1994-1999
Postdoctoral trainee with Dr. Ted Hansen, Washington University in St. Louis, 1989-1994

Honors and Awards

Member, NIH Study Section: The Pathogenic Eukaryotes, 2009-present
Associate Editor, Plos Pathogens, 2006-present
Ellison Medical Foundation New Investigator Award in Global Infectious Diseases, 2001
National Foundation for Infectious Diseases New Investigator Award, 2000
Spencer T. and Ann W. Olin Medical Scientist Fellow, awarded in recognition of superior achievement in biomedical research, 1993

Field of Study

I first became interested in a career in science from the encouragement of a college instructor. For graduate school, I studied how MHC class I molecules bind peptide antigens and present them to the cellular immune system. This process is fundamental to the recognition and elimination of pathogens and also has medical implications for organ transplantation and rejection.

Following graduate school, I became interested in malaria research and trained at the Laboratory of Parasitic Diseases at the National Institutes of Health. My current work focuses on antigenic variation and cytoadherence in Plasmodium falciparum malaria. These processes enable parasites to evade immunity and cause disease.

Publications

2012

High Levels of Antibodies to Multiple Domains and Strains of VAR2CSA Correlate with Absence of Placental Malaria in Cameroonian Women Living in a High Plasmodium falciparum Transmission Area

[8]

2011

Branch point identification and sequence requirements for intron splicing in Plasmodium falciparum

[9]

Investigating the Host Binding Signature on the Plasmodium falciparum PfEMP1 Protein Family

[10]

Antibodies to a Full-Length VAR2CSA Immunogen Are Broadly Strain-Transcendent but do not Cross-Inhibit Different Placental-Type Parasite Isolates

[11]

Induction of strain-transcendent antibodies to placental-type isolates with VAR2CSA DBL3 or DBL5 recombinant proteins

[12]

2010

Identification of a Role for the PfEMP1 Semi-Conserved Head Structure in Protein Trafficking to the Surface of Plasmodium falciparum Infected Red Blood Cells.

[13]

Immunization with VAR2CSA-DBL5 recombinant protein elicits broadly cross-reactive antibodies to placental-type Plasmodium falciparum infected erythrocytes [14]

Evaluation of the antigenic diversity of placenta-binding Plasmodium falciparum variants and the antibody repertoire among pregnant women [15]

Advances and challenges in malaria vaccine development [16]

2009

Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris

[17]

2008

Evidence for globally shared, cross-reacting polymorphic epitopes in the pregnancy-associated malaria vaccine candidate VAR2CSA

[18]

VAR2CSA domains expressed in Escherichia coli induce cross-reactive antibodies to native protein

[19]

VAR2CSA domains expressed in E.coli induce cross-reactive antibodies to native protein

[20]

2007

Structural polymorphism and diversifying selection on the pregnancy malaria vaccine candidate VAR2CSA

[21]

Antigenic variation in Plasmodium falciparum: gene organization and regulation of the var multigene family

[22]

Pregnancy-associated malaria: parasite binding, natural immunity and vaccine development

[23]

Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates

[24]

Disruption of var2csa gene impairs placental malaria associated adhesion phenotype

[25]

2006

Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria

[26]

A family affair: var genes, PfEMP1 binding, and malaria disease

[27]

Disguising itself--insights into Plasmodium falciparum binding and immune evasion from the DBL crystal structure

[28]

Mapping a common interaction site used by Plasmodium falciparum Duffy binding-like domains to bind diverse host receptors

[29]

2004

Pregnancy-associated malaria and the prospects for syndrome-specific antimalaria vaccines

[30]

Functional interdependence of the DBLbeta domain and c2 region for binding of the Plasmodium falciparum variant antigen to ICAM-1

[31]

2003

Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family

[32]

New tools to identify var sequence tags and clone full-length genes using type-specific primers to Duffy binding-like domains

[33]

1997

Stable azole drug resistance associated with a substrain of Candida albicans from an HIV-infected patient

[34]

Staff

Jay Brazier, Research Associate

Marion Avril, Staff Scientist

Martin Melcher, Postdoctoral Scientist

Sowmya Sampath, Postdoctoral Scientist

Accomplishments & Collaborations

Lab Accomplishments

Developed binding assays and computational approaches to investigate the parasite cytoadherent receptors responsible for infected erythrocyte sequestration and disease.
Completed first inter-strain comparison of var gene repertoires.
Characterized the PfEMP1 protein involved in placental binding that is being developed as a vaccine for malaria during pregnancy.