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Mechanisms of vaccine protection against AIDS-associated Cryptococcus infection

疫苗预防艾滋病相关隐球菌感染的机制

基本信息

批准号：
10793773
负责人：
Amariliz Rivera
金额：
$ 2.27万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-05 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10793773
关键词：
Acquired Immunodeficiency Syndrome Affect Antifungal Agents Attenuated Biological Response Modifiers CD4 Positive T Lymphocytes CD8B1 gene Cell surface Cells Cessation of life Clinical Complex Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Cryptococcus neoformans infection Development Disease F-Box Proteins Fungal Meningitis Future Gene Targeting Genetic Goals HIV Hybrids Immune Immune response Immune system Immunity Immunotherapy Inactivated Vaccines Infection Infection Control Innate Immune Response Interferon Type II Life Link Lung Lung infections Masks Mediating Mediator Medical Modeling Molecular Mouse Strains Mus Mycoses Neutrophil Infiltration Opportunistic Infections Outcome Pathway interactions Patients Phenotype Population Preparation Preventative vaccination Production Proteins Publishing Reporter Role Safety Series Shapes Siblings Source T cell response T-Lymphocyte Testing Ubiquitin Vaccination Vaccine Design Vaccines Virulence Virulence Factors Virulent Work adaptive immune response cellular targeting cost cross immunity follow-up gain of function immunogenic immunogenicity immunoregulation improved in vivo inhibitor insight loss of function monocyte mutant neutrophil novel novel therapeutic intervention novel vaccines pathogen pathogenic fungus patient population protein degradation recruit response success transdifferentiation ubiquitin-protein ligase vaccination strategy vaccine candidate vaccine-induced immunity

项目摘要

Abstract Cryptococcosis is an AIDS-defining illness and the most common fungal disease in HIV-infected patients. Most cases of fungal meningitis in AIDS patients are due to infections with the globally distributed fungal pathogen Cryptococcus neoformans. Recent estimates indicate that C.neoformans causes > 180,000 deaths annually and is responsible for 15% of AIDS-related deaths. Thus, there is a significant, unmet medical need to develop new treatments against this life-threatening fungal infection. A better understanding of host and pathogen factors that shape immunity against Cryptococcus can inform the development of much needed preventative vaccination strategies and immune-based therapies. In recently published studies, we have uncovered that F-box protein 1 (Fbp1) acts as a regulator of C. neoformans immunogenicity. Fbp1 is a subunit of the SCFFbp1 E3 ligase complex, a key component of the ubiquitin-mediated proteolytic pathway that targets specific proteins for degradation. The C. neoformans mutant strain lacking Fbp1 (fbp1D) is hypovirulent in vivo without affecting the expression of known virulence factors, indicating that Fbp1 likely regulates a novel virulence determinant. Pulmonary infection with fbp1D induced the robust recruitment of CCR2+ monocytes and the activation of enhanced CD8+ and CD4+ T cell responses. We uncovered that these enhanced innate and adaptive immune responses cooperate to control C. neoformans infection in the lung and are both required for the long-term survival of the host. Moreover, heat-killed preparations of the fbp1D mutant (HK-fbp1D) acted as an effective vaccine and protected mice of two different genetic backgrounds against infection with the parental, highly virulent strain H99. In this application, we propose a series of collaborative studies to decipher how Fbp1 regulates the activation of anti-Cryptococcus immunity and to further exploit the potential of fbp1D as a novel vaccine strain against cryptococcosis. The central hypothesis of our work is that Fbp1 regulates the abundance of specific target proteins, which in turn shape the immunogenicity of C. neoformans. Our overarching goal is to systematically decipher the immune mechanisms of vaccine-induced protection and to identify and validate specific Fbp1-regulated targets that shape the immunogenicity of C. neoformans. We will utilize our combined expertise to test our hypothesis in three independent, but closely related Specific Aims: 1) Decipher the distinct contributions of innate immune cell populations to protection from infection with fbp1D and to HK-fbp1D vaccine-induced protection, 2) Uncover the molecular mechanisms of IFN-g-mediated vaccine protection, and 3) Identify and validate Fbp1- regulated targets that influence host immunity. In aggregate, these studies will advance our understanding of host-pathogen interactions involved in the immune regulation by Cryptococcus and may guide the design of vaccines and inhibitors of specific C. neoformans factors to enhance host-mediated control of infection.

摘要