Novel Candida albicans host receptors during infection and immune response

感染和免疫反应期间新型白色念珠菌宿主受体

• 批准号: 10231043
• 负责人: Marc Swidergall
• 金额: $ 23.67万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231043
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Advisory Committees; Antifungal Agents; Azole resistance; Azoles; Binding; Candida albicans; Cell Wall; Cells; Committee Members; Complement; Data; Diabetes Mellitus; Disease; Elements; Endocytosis; Eph Family Receptors; Ephrins; Epithelial; Epithelial Cells; Esophagus; Faculty; Filler; Future; Goals; Head Cancer; Head and Neck Cancer; Host Defense; Human; Immune; Immune response; Immunocompromised Host; In Vitro; Individual; Industrial fungicide; Infection; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-17; Invaded; Leukocytes; Life; Ligands; Liver; MAP Kinase Gene; Mentors; Modeling; Molecular; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mus; Myeloid Cells; Neutropenia; Opportunistic Infections; Oral; Oral mucous membrane structure; Organism; Particulate; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Peptides; Phagocytes; Phase; Phosphorylation; Play; Population Heterogeneity; Positioning Attribute; Postdoctoral Fellow; Process; Public Health; Receptor Activation; Receptor Cell; Research; Research Institute; Research Personnel; Research Training; Role; Scientist; Senior Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Sjogren' s Syndrome; Stat3 protein; Steroids; Structure; Surface; Testing; The science of Mycology; Training; Zymosan; beta-Glucans; beta-glucan receptor; career; career development; cytokine; design; experience; fungal microbiota; fungus; improved; in vivo; interest; laminaran; neutrophil; novel; novel strategies; novel therapeutic intervention; novel therapeutics; oral cavity epithelium; oral fungal; oropharyngeal thrush; pathogen; patient population; prevent; professor; receptor; response; student training

ABSTRACT/SUMMARY The polymorphic fungus, Candida albicans is part of the endogenous human mycobiota. It colonizes mucosal surfaces of 30-70% of healthy individuals. The fungus causes both superficial mucosal diseases and life threatening invasive infection. Oropharyngeal candidiasis (OPC) causes significant morbidity in a large and diverse population of patients, including those with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, cancer of the head and neck, or the use of steroids Nearly 10 million cases of HIV/AIDS associated OPC occur annually and nearly one fifth of these cases have esophageal involvement. To cause OPC, C. albicans must adhere to and invade the oral mucosa, and resist being killed by host phagocytes. Dr. Swidergall discovered that EphA2 on oral epithelial cells and neutrophils is a novel pattern recognition receptor for C. albicans. EphA2 binds exposed β-glucan on the fungal cell walls, and the preliminary data indicate that it plays a key role in the response of both epithelial cells and neutrophils to the organism. The central objective of this proposal is to determine how the β-glucan receptor EphA2 interacts with other host signaling molecules to induce an inflammatory response in both the oral mucosa and leukocytes, and induce oral epithelial cell invasion during OPC. Aim 1 will evaluate the role of EphA2 activation and downstream signaling in oral epithelial cells during oral C. albicans infection in vitro and in vivo. Aim 2 will characterize the mechanisms by which EphA2 activation triggers neutrophil fungicidal activity. The long-term goal of this research is to determine how host receptors recognize invading fungi and maintain mucosal immunity so that new drugs and strategies to treat and prevent fungal diseases can be developed. The candidate, Dr. Swidergall, has a longstanding interest in mycology research. After completing the mentored phase of this K99, his goal is to become an assistant professor at a leading academic research institute, where he plans to continue his research on the role of critical host cell receptors in the pathogenesis of OPC. He also plans to teach students and train future scientists. This K99/R00 proposal is designed to complement Dr. Swidergall's prior research training and provide him with the necessary technical and intellectual expertise to become an independent investigator. The training he will receive in the K99 phase will substantially enhance his career prospects, and make him highly competitive for faculty positions in top research institutes. Dr. Swidergall's primary mentor, Dr. Scott G. Filler, and co-mentor, Dr. Michail S. Lionakis, were carefully selected for their relevant, diverse, and complementary expertise to cover all elements of his proposal. In addition, Dr. Swidergall has assembled an advisory committee of a diverse group of scientists to oversee his scientific progression and career development during his transition to an independent investigator. All members of this committee are senior scientists with extensive experience in mentoring postdocs.

抽象/总结

项目成果

Mucosal IgA Prevents Commensal Candida albicans Dysbiosis in the Oral Cavity.

• DOI: 10.3389/fimmu.2020.555363
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Millet N;Solis NV;Swidergall M
• 通讯作者: Swidergall M

Immunosurveillance of Candida albicans commensalism by the adaptive immune system.

• DOI: 10.1038/s41385-022-00536-5
• 发表时间: 2022-05
• 期刊: MUCOSAL IMMUNOLOGY
• 影响因子: 8
• 作者: Swidergall, Marc;LeibundGut-Landmann, Salome
• 通讯作者: LeibundGut-Landmann, Salome

Rapid proliferation due to better metabolic adaptation results in full virulence of a filament-deficient Candida albicans strain.

• DOI: 10.1038/s41467-021-24095-8
• 发表时间: 2021-06-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Dunker C;Polke M;Schulze-Richter B;Schubert K;Rudolphi S;Gressler AE;Pawlik T;Prada Salcedo JP;Niemiec MJ;Slesiona-Künzel S;Swidergall M;Martin R;Dandekar T;Jacobsen ID
• 通讯作者: Jacobsen ID