Understanding innate immunity in fungi

了解真菌的先天免疫

• 批准号: 10218397
• 负责人: Teresa E Pawlowska
• 金额: $ 23.55万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218397
• 关键词: Address; Animals; Anti-Bacterial Agents; Apoptosis; Bacteria; Bacterial Infections; Biological Models; Cell Death; Cell Wall; Cell physiology; Cells; Chromosome Mapping; Clinical; Data; Disease; Environment; Evolution; Foundations; Fungi Model; Future; Genes; Genetic Screening; Genomics; Goals; Health; Human; Immune; Immunotherapeutic agent; Incidence; Individual; Infection; Invaded; Knowledge; Metabolism; Microbe; Modification; Molecular; Mucor; Mucormycosis; Mycoses; Natural Immunity; Organism; Outcome; Patients; Perception; Pharmacology; Plants; Process; RNA Interference; Reaction; Reactive Oxygen Species; Reproduction; Resistance; Respiratory Burst; Role; Signal Transduction; System; Testing; Therapeutic; Work; Wound Infection; antimicrobial; antimicrobial drug; base; defense response; fungus; gene function; insight; mortality; mutant; mutualism; novel; opportunistic pathogen; plant fungi; prevent; programs; response; sensor; small molecule; targeted treatment; tool; traumatic wound; treatment strategy

PROJECT SUMMARY The goal of this exploratory work is to develop foundations for understanding innate immunity defenses in Mucoromycotina fungi, with a particular focus on the mechanisms triggering programmed cell death (PCD). We expect that these processes will become future targets for controlling mucormycoses, which are human infections caused by Mucoromycotina. Mucormycoses are increasingly frequent, highly destructive, and often fatal in immune-compromised individuals. Some clinical isolates of Mucoromycotina harbor endosymbiotic bacteria (EB) that can be isolated and cultivated independently. Our recent work generated insights into fungal responses to such isolated EB that were perceived by fungi as mutualists versus antagonists. In mutualisms, bacteria enter fungal cells and manipulate cellular processes of permissive hosts. In antagonisms, bacterial infections of non-host fungi are blocked by fungal responses that resemble innate immunity of animals and plants. In animals and plants, innate immunity mechanisms prevent bacterial invasions of cellular environment and suppress those invasions by initiating PCD. To accomplish our goal of unraveling novel mechanisms of innate immunity in Mucoromycotina, we will use isolated EB as a tool to elicit fungal defense responses. We will test whether Mucoromycotina are able to: (i) sense microbes, (iii) deploy defense modules that prevent bacterial entry, and (iii) when faced with bacteria capable of breaching these primary defenses, trigger PCD to eliminates intruders. To test these hypotheses, we will address the following specific aims: (1) determine the roles of candidate innate immunity sensors in bacterial infection of non-host strains and (2) identify novel genes responsible for elimination of bacterial infections, including genes that control defense and PCD modules. In addition to their profound health impacts, Mucoromycotina present a remarkably convenient study system for elucidating fungal-bacterial interactions in polymicrobial disorders. Expected outcomes of the project include determination of the molecular bases of fungal innate immunity and PCD, which, in the future, could be targeted to eradicate Mucoromycotina infections.

项目摘要 这项探索性工作的目的是为了解先天免疫防御的基础开发 粘膜瘤真菌，特别关注触发程序性细胞死亡（PCD）的机制。 我们预计这些过程将成为控制粘肌的未来目标，这是人类 由粘膜瘤引起的感染。粘液酸越来越频繁，具有高度破坏性，并且经常 在免疫受损的个体中致命。 粘膜瘤的一些临床分离株可以分离出来，并且可以分离出来 独立种植。我们最近的工作对这种孤立的EB的真菌反应产生了见解 真菌将真菌视为共同主义者与拮抗剂。在互助中，细菌进入真菌细胞和 操纵允许宿主的细胞过程。在对抗中，非宿主真菌的细菌感染是 被类似于动物和植物的先天免疫力的真菌反应阻塞。在动物和植物中， 先天免疫机制可防止细菌入侵细胞环境并抑制这些入侵 通过启动PCD。 为了实现我们揭开粘膜菌具有新颖的先天免疫机制的目标，我们将使用 孤立的EB作为引起真菌防御反应的工具。我们将测试Mucoromycotina是否能够：（i） 感官微生物，（iii）部署防止细菌进入的防御模块，并且（iii）面对细菌 能够违反这些主要防御能力，触发PCD消除入侵者。为了检验这些假设， 我们将解决以下具体目的：（1）确定候选人先天免疫传感器的作用 非宿主菌株的细菌感染和（2）鉴定出负责消除细菌的新基因 感染，包括控制防御和PCD模块的基因。 除了对健康的深远影响外，粘膜瘤也提出了一个非常方便的研究系统 用于阐明多因素疾病中的真菌 - 细菌相互作用。该项目的预期结果 包括确定真菌先天免疫和PCD的分子基础，将来可能是 旨在消除粘膜瘤感染。