R01AI176922

Continuum of Immune Responses to Cryptococcus neoformans - Abstract

Cryptococcal meningitis (CM), caused by the fungal pathogen Cryptococcus neoformans (CN), is among the most prevalent HIV/AIDS-associated opportunistic infections and causes 15% of AIDS-related mortality globally.

In healthy individuals, exposure to CN in early childhood results in a pulmonary latent infection that is asymptomatic, but leads to the formation of lung granulomas. Following HIV-associated compromise of the immune system, control of latent CN infection within pulmonary granulomas is lost and the fungus disseminates to cause meningitis.

Most studies examining host-pathogen interactions in CN are observational studies in human cohorts or analyze reference CN strains in acute disease models of cryptococcosis. We recently showed that the mouse model accurately recapitulates differences in human survival that are observed across CN clinical isolates and used these data to develop a mouse model of latent CN infection.

Our preliminary data using these mouse models to analyze the immune response to over 50 CN clinical isolates from individuals with advanced HIV revealed a continuum of disease outcomes that we classified into 3 groups: 1) latent infection resulting in granuloma formation and control; 2) lethal disease similar to that observed with CN reference strains; and 3) hypervirulence resulting in rapid mortality.

Previous studies with reference strains revealed lethal disease is associated with various CN virulence factors and a detrimental host TH2-mediated type-2 immune response. In contrast, disease prevention is associated with the type-1 cytokine IFN. How these CN-host interactions differ to cause the continuum of disease observed in immunocompromised individuals with HIV is not well defined.

We will use analysis of clinical isolates in mouse models of disease to test our central hypothesis that antigenic differences between CN clinical isolates lead to either protective or detrimental immune responses in the host. We will test this hypothesis by pursuing three specific aims.

Our first and second aims will determine the host cellular and effector functions that result in either latency (Aim 1), lethal disease (control infections), or hypervirulence (Aim 2). Our third aim will identify CN gene alleles for antigens that influence the immune response and ultimately disease outcome.

Taken together, these translational studies will define the molecular processes underlying the continuum of Cryptococcus disease with the goal of developing novel immune-modulatory treatment strategies for at-risk patient populations.

Virginia Polytechnic Institute & State University

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]

Blacksburg, Virginia 240603831 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 310% from $737,302 to $3,024,157.