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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：
10274411
负责人：
Amariliz Rivera
金额：
$ 4.86万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10274411
关键词：
Acquired Immunodeficiency Syndrome Affect Alveolar Macrophages Antifungal Agents Aspergillosis Aspergillus fumigatus Candida albicans Cells Cessation of life Clinical Complement Critical Pathways Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Data Defect Effector Cell Exposure to Fungal Drug Resistance Fungal Vaccines Gene Targeting Goals Grant Growth HIV Health Human Immune Immune response Immunity Immunocompromised Host Immunosuppressive Agents In Vitro Individual Infection Infection Control Inflammation Instruction Interferons Intervention Life Lung Lung infections Lymphoid Maps Mediator of activation protein Medical Mus Mycoses Myeloid Cells Opportunistic Infections Outcome Pathogenicity Patients Phagocytes Population Preparation Production Publishing Recording of previous events Research Risk Role STAT1 gene Shapes Siblings Signal Transduction Source Testing Therapeutic Tissues Training Vaccination Vaccines Yeasts base chemotherapy immunogenic improved in vivo insight loss of function macrophage monocyte mortality mutant neutrophil novel novel therapeutic intervention novel vaccines pathogen pathogenic fungus programs response vaccine candidate vaccine-induced immunity

项目摘要

ABSTRACT Fungal infections are often an under recognized pathogenic cause of host mortality. The rise in use of immunosuppressant therapeutics over the past decades has resulted in the steady increase of susceptible populations throughout the world. Moreover, mortality rates from invasive fungal infection remain unacceptably high due to the frequent inability of antifungal drugs to efficiently control fungal growth. Currently no fungal vaccines exist even as host mortality rates due to pathogenic fungi including Aspergillus fumigatus (Af), Cryptococcus neoformans (Cn), and Cryptococcus gatti (Cg), continue to increase. Therefore, there is a clear medical need for antifungal vaccines that can help protect susceptible populations. In previous studies we determined that heat-killed preparations of Cn-fbp1 (HK-Fbp1) mutant yeast cells can function as an effective and novel vaccine candidate. Furthermore, we recently uncovered that vaccination with HK-Fbp1 can confer cross-protection against different fungal species including A. fumigatus, C. albicans, and C. gatti. These findings suggest that upon HK-Fbp1 vaccination there is activation of conserved antifungal mechanisms that can protect against diverse fungal species. In the studies proposed in this supplement we seek to expand on the goals of the parental grant to focus on deciphering the mechanisms of vaccine-induced cross-protection against Af. We hypothesize that vaccination with HK-Fbp1 confers defense against Af via activation of trained innate immune cells. The concept of innate immune training has become a growing and exciting field of research. Various studies support the notion that the host’s history of infection can affect responses to exposure to subsequent infections. In previous studies the Rivera lab demonstrated that defense against Af is dependent on myeloid cells and can occur even in the absence of the entire lymphoid compartment. Thus, we hypothesize that this novel HK-Fbp1 vaccine confers protection against Af infection via trained immunity of myeloid cells. We will investigate this hypothesis via the following independent aims: 1) Decipher the roles of innate cells in HK-Fbp1, vaccine- induced protection against fungal challenges, and 2) Define the role of IFN signaling in the instruction of antifungal, pulmonary trained innate cells. These proposed studies will complement and expand the scope of the parental grant to provide novel insight on how HK-Fbp1 vaccine shapes broadly protective antifungal defense. These studies will further advance the search for a pan-fungal vaccine.

摘要