Innate control of the inflammatory process during fungal infections

真菌感染期间炎症过程的先天控制

• 批准号: 10641775
• 负责人: Ivan Zanoni
• 金额: $ 51.38万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641775
• 关键词: Address; Adjuvant; Affect; Allergic Disease; Anatomy; Antibodies; Antibody Formation; Antifungal Agents; Antigens; Attention; Autoimmune Diseases; B-Lymphocytes; Binding; Bypass; C Type Lectin Receptors; Candida; Candida albicans; Candidiasis; Cell Wall; Cells; Centers for Disease Control and Prevention (U.S.); Data; Detection; Development; Disease; Epithelium; Event; Gene Mutation; Genetic Transcription; Goals; Health; Immune; Immune response; Immune system; Immunocompromised Host; Immunology; Incidence; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferon Type II; Interferons; Life; Ligands; Location; Lymph Node Subcapsular Sinus; Macrophage; Mediating; Medical; Modeling; Modernization; Mycoses; NF-kappa B; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Peripheral; Persons; Phagocytes; Polysaccharides; Predisposition; Process; Production; Role; Sentinel; Sepsis; Signal Transduction; Solubility; Stimulus; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Vaccines; adaptive immune response; adaptive immunity; autoimmune pathogenesis; candidemia; design; draining lymph node; fungus; genetic signature; global health; improved; inflammatory milieu; innovation; insight; microbial; migration; novel; novel therapeutic intervention; pathogen; physical property; prevent; protein function; relB protein; response; therapeutically effective

PROJECT SUMMARY The dialogue between innate and adaptive branches of the immune system is a central paradigm of modern immunology and is vital for protection against infections as well as for the pathogenesis of autoimmune, allergic and inflammatory diseases. According to the current model, innate immune sentinels dispersed throughout peripheral tissues sense, via their pattern recognition receptors (PRRs), the presence of microbial clues or endogenous moieties released during an infection, are activated and migrate to the draining lymph node (dLN). This process enables a transfer of “information” from peripheral tissue to the dLN, where the antigen-dependent adaptive immune response against the pathogen is initiated. The dLN also hosts an initial antigen-independent, innate immune response governed by migrating phagocytes that enables expansion of the LN and establishes a pro-inflammatory milieu. These events are required for the development and polarization of the adaptive immune response. Here, we focused our attention on the capacity of ligands derived from the cell wall of Candida (C.) albicans to dictate the LN innate response. Our working hypothesis is that the size and solubility of stimuli that activate the PRRs affect not only the LN innate response itself, but also the final outcome of the immune response. Also, that the LN innate response initiated by soluble fungal ligands can be harnessed to develop a potent and protective adaptive immune response to prevent life-threatening systemic fungal infections. Our preliminary data demonstrate that the physical form of fungal ligands dictates the location where the initial immune response takes place, and thereby determines the activation of adaptive immunity. In particular, we have found that small soluble fungal ligands that are immunosilent in the periphery and do not cause an inflammation in the tissue, become potent immunogens once they reach the dLN. Also, that the LN innate response initiated by these ligands completely bypasses the need of phagocyte migration from the periphery into the dLN and, instead, requires a unique gene signature that is characterized by the production of interferons and that is driven by the activation of the noncanonical NFkB transcription factor RelB in subcapsular sinus macrophages. Notably, Dectins are required for this process but CARD9, the key signaling adaptor downstream of Dectins, is largely dispensable. Plus, the initial innate response to the dLN instructs a potent type 1 adaptive immunity and allows the production of antibodies directed against the most external layer of the fungal cell wall. Fungal diseases are a global health problem and Candida species are the most common cause of invasive fungal infections. We propose to unravel how physical properties of the PAMPs can be harnessed as a therapeutic intervention against systemic fungal infections that are a major medical problem in the US. We anticipate that identifying new features of the immune response that is anatomically restricted to the LN will help with the design of an improved vaccine against poorly controlled pathogens.

项目总结

项目成果

Microbiome studies in the medical sciences and the need for closer multidisciplinary interplay.

医学中的微生物组研究以及更密切的多学科相互作用的需要。

• DOI: 10.1126/scisignal.aba9911
• 发表时间: 2020
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Mancini,Nicasio;Peri,Francesco;Rescigno,Maria;Zanoni,Ivan
• 通讯作者: Zanoni,Ivan

μMAPPS: a novel phasor approach to second harmonic analysis for in vitro-in vivo investigation of collagen microstructure.

• DOI: 10.1038/s41598-017-17726-y
• 发表时间: 2017-12-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Radaelli F;D'Alfonso L;Collini M;Mingozzi F;Marongiu L;Granucci F;Zanoni I;Chirico G;Sironi L
• 通讯作者: Sironi L

Immunobiology of Carbohydrates: Implications for Novel Vaccine and Adjuvant Design Against Infectious Diseases.

• DOI: 10.3389/fcimb.2021.808005
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Stefanetti G;Borriello F;Richichi B;Zanoni I;Lay L
• 通讯作者: Lay L

Editorial: Interferon-λs: New Regulators of Inflammatory Processes.

社论：干扰素：炎症过程的新调节器。

• DOI: 10.3389/fimmu.2019.02117
• 发表时间: 2019
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Zanoni,Ivan;Odendall,Charlotte
• 通讯作者: Odendall,Charlotte

Host-derived oxidized phospholipids initiate effector-triggered immunity fostering lethality upon microbial encounter.

宿主来源的氧化磷脂启动效应子触发的免疫，在微生物遭遇时产生致命性。

• DOI: 10.1101/2023.11.21.568047
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Gioia,MarcoDi;Poli,Valentina;Tan,PiaoJ;Spreafico,Roberto;Chu,Anne;Cuenca,AlexG;Gordts,PhilipLsm;Pandolfi,Laura;Meloni,Federica;Witztum,JosephL;Chou,Janet;Springstead,JamesR;Zanoni,Ivan
• 通讯作者: Zanoni,Ivan