NK Cell Cytotoxicity Against Cryptococcus neoformans in Persons with Advanced HIV and Cryptococcal Meningitis

NK 细胞对晚期 HIV 和隐球菌性脑膜炎患者的新型隐球菌的细胞毒性

• 批准号: 10543405
• 负责人: Elizabeth Okafor
• 金额: $ 4.18万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543405
• 关键词: Activated Natural Killer Cell; Acute; Adult; Affect; Africa; Africa South of the Sahara; Antibodies; Antifungal Therapy; Antigens; CD4 Positive T Lymphocytes; CXCL10 gene; CXCR3 gene; Cell Separation; Cell physiology; Cell surface; Cell-Mediated Cytolysis; Cells; Central Nervous System Infections; Chronic; Clinical; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Cytokine Receptor Gene; Data; Defect; Diagnosis; Disease; Disease Progression; Functional disorder; Future; Gene Expression; Genes; Goals; Granzyme; HIV; HIV Infections; Human; IL2RB gene; Immune; Immune response; Immune signaling; Immunocompromised Host; Immunotherapy; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Interferon Type II; Life; Lymphoid; Meninges; Meningitis; Molecular; Morbidity - disease rate; Mycoses; Natural Killer Cells; Ontology; Pathway Analysis; Pathway interactions; Patients; Pattern; Persons; Phenotype; Physiological; Predisposition; Production; Receptor Signaling; Research; Resolution; Risk; Role; Signal Pathway; Signal Transduction; Solid; Sterility; Symptoms; TNFSF10 gene; Technology; Testing; Therapeutic; Translating; Virus Diseases; adaptive immune response; antibody-dependent cell cytotoxicity; antiretroviral therapy; arm; brain parenchyma; burden of illness; cytokine; cytotoxic; cytotoxicity; differential expression; exhaustion; extracellular; immune modulating agents; improved; innovation; lonely individuals; low income country; mortality; pathogen; pathogenic fungus; receptor; receptor expression; targeted treatment; transcriptome; transcriptome sequencing

PROJECT SUMMARY / ABSTRACT Cryptococcus neoformans is an opportunistic fungal pathogen that causes localized and disseminated disease, cryptococcosis, in immunocompromised individuals, such as in people living with HIV. A life- threatening manifestation of cryptococcosis is cryptococcal meningitis (CM); a central nervous system infection with acute inflammation of the meninges and the most common cause of meningitis in those with HIV. Sub- Saharan Africa carries the majority of the global CM disease burden and mortality. Because the host immune response is crucial to clearance of the infection and resolution of symptoms, a solid understanding of the host immune response in the state of cryptococcal infection is essential in order to reduce morbidity and mortality. Natural killer (NK) cells are an innate lymphoid immune cell that has been understudied in CM. NK cells have antigen independent cytotoxic ability that render them ideal for targeting both intracellular and extracellular pathogens. This key feature of NK cells could make them an important aspect in the immune response to C. neoformans, which is both an intracellular and extracellular pathogen. Standard antifungal therapy targets the pathogen, yet mortality still occurs, including among persons with sterile CSF cultures. My preliminary data has shown that low CSF concentrations of NK cell cytotoxicity associated soluble molecules are associated with increased risk of acute 14-day mortality in persons with CM. Therefore, improving NK cytotoxic activity may be an innovative therapeutic pathway toward reducing cryptococcal mortality. Additionally, the identification of genes and pathways implicated in impaired NK cell function that could be modulated to improve cytotoxicity could be targets for future therapeutics. My central hypothesis is that NK cells contribute to fungal clearance of C. neoformans, but that a combination of NK cell exhaustion, impaired cytokine production, increased inhibitory receptors, and decreased activating receptor expression due to the underlying HIV infection disrupts their cytotoxic abilities. To test the central hypothesis, I am proposing the following Aims: Aim 1 seeks to compare NK cell natural cytotoxicity and antibody-dependent cell mediated cytotoxicity between HIV-infected persons with CM who die within 14-days of diagnosis and those who survive >14 day. Aim 2 seeks to determine if persons with CM who die within 14-days have high levels of differentially expressed genes involved in exhaustion and inhibition of cytotoxicity pathways when compared to persons who survive CM. Collectively, these findings will provide the first quantification of NK cell cytotoxicity against clinical isolates of C. neoformans and the identification of differentially expressed genes associated with acute CM mortality. This information will provide us with specific genes that are involved in exhaustion, cytokine production, and cytotoxicity that could be modulated in the future with host targeted immunotherapy.

项目摘要/摘要