R01AI167422

Pathogenic Low Affinity CD8 T Cells in Malaria

The focus of the research in the Lamb Lab is to determine mechanisms of the immunopathogenesis of malaria. The Evavold Lab is one of the leading laboratories working in T cell biology with the capability to precisely measure the affinity profile of polyclonal T cell populations. Together, we will address the long-term goal of this proposal, which is to define the salient features of the T cell response during Plasmodium infections that drive the pathology of malaria.

It is estimated that annually more than 500 million people are infected with malaria worldwide, resulting in 0.5 million deaths. T cell responses against the Plasmodium parasites that cause malaria are critical in orchestrating immune effector mechanisms such as phagocytosis and antibody production to control parasitemia. However, T cells are also responsible for the pathogenesis of infection. The features that determine beneficial versus pathogenic T cells in malaria are incompletely understood.

Here, we propose that the affinity of CD8 T cells reacting to Plasmodium peptides shapes the repertoire of expanded cells and profoundly alters their function, in turn impacting pathogenesis. Although others have identified T cell epitopes that are immunodominant in Plasmodium infections, we know very little about the antigen reactivity profile of these pathogenic T cells as infection progresses.

In general, it is believed that high affinity T cells predominate any polyclonal T cell response, yet this is not supported by our preliminary data, which clearly shows that low affinity T cells make up more than 80% of the pathogenic anti-Plasmodium response. Based on our preliminary data, we hypothesize that this predominance of low affinity CD8 T cells is a unique feature of Plasmodium infection that leads to organ-specific damage because CD8 T cells with low affinity T cell receptors induce different responses in cross-presenting brain microvascular endothelial cells (BMECs) compared with high affinity CD8 T cells.

The rationale for the proposed work is that T cell responses are central to the organ-specific attack associated with malaria, and a more comprehensive understanding of the T cell response will provide key information for the rational use and design of novel anti-malaria interventions as well as future vaccines.

We plan to test our central hypothesis and, thereby, accomplish the objective of this application, by pursuing the following three specific aims:

Aim 1: Demonstrate that low affinity CD8 T cells are pathogenic in experimental cerebral malaria.

Aim 2: Define the functional differences between low and high affinity CD8 T cells trafficking to the central nervous system (CNS) in Plasmodium infection.

Aim 3: Test the hypothesis that low affinity CD8 T cells predominate the response based on the context of how the parasite antigens are recognized.

University Of Utah

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Salt Lake City, Utah 841121100 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 399% from $653,615 to $3,264,359.