R01AI167058

Mechanisms and Consequences of Extrafollicular B Cell Activation During Malaria - Abstract

There is currently a lack of mechanistic understanding of why humoral immunity against malaria is not efficiently induced and why Plasmodium infections are associated with immune failures, even following repeated infections. Our long-term goal is to determine how Plasmodium parasites, and potentially other protozoan infections, co-opt and subvert humoral immunity, which will help with the identification and development of new immune-based interventions against devastating diseases like malaria.

The objectives of this project are to define mechanisms that trigger initial humoral immune dysregulation and study the consequences of these events on the formation of durable humoral immune memory. Our central hypothesis is that robust humoral immunity does not develop efficiently because polyclonal B cell activation events establish a nutrient sink that impairs the metabolic, transcriptional, and epigenetic programming and function of Plasmodium-specific memory B cells.

The rationale for this project is linked to our recent discovery that Plasmodium infection results in a massive polyclonal expansion of B cells that function as a nutrient sink, limiting protective memory B cell responses. Deletion of these B cells accelerates blood-stage Plasmodium parasite clearance and enhances humoral immune memory. Supplementing the diet of infected mice with a single amino acid is sufficient to overcome the nutrient sink and metabolic constraints imposed by these B cells, resulting in enhanced humoral immune memory responses.

Despite our new findings, the molecular mechanisms governing the activation and function of immunoinhibitory B cells and the impact of these cells on the affinity and longevity of memory B cells remain critical knowledge gaps in our quest to improve humoral immunity against malaria. Two aims address these priority questions. In the first aim, we will determine the molecular and cellular mechanisms that govern the expansion of these immunosuppressive B cells and investigate whether these populations are relevant to other infections associated with dysregulated humoral immunity. In the second aim, we will investigate the molecular and cellular consequences of immunosuppressive B cell expansions on the genetic and epigenetic programming of memory B cells.

We have developed several innovative new reagents that afford unprecedented resolution for the study of anti-malarial humoral immunity. The significance of this project is directly linked to our new findings showing that pathophysiological changes that occur during Plasmodium infection durably imprint on B cell fate and function. Thus, determining how these pathways coordinately regulate polyclonal B cell activation, development, and humoral immunity will be broadly important to those studying infectious disease immunology and vaccinology.

The University Of Iowa

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]

Iowa City, Iowa 52242 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 400% from $647,119 to $3,235,595.