Understanding innate immunity in fungi

了解真菌的先天免疫

基本信息

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
项目类别：
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

项目摘要

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.

项目概要这项探索性工作的目标是为理解先天免疫防御奠定基础毛霉菌亚门真菌，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人类毛霉菌病的未来目标由毛霉菌亚门引起的感染。毛霉菌病越来越频繁，具有高度破坏性，并且经常对于免疫功能低下的个体来说是致命的。毛霉菌门的一些临床分离株含有内共生细菌 (EB)，可以将其分离和独立培养。我们最近的工作深入了解了真菌对这种孤立的 EB 的反应，被真菌视为互利共生者与拮抗者。在互利共生中，细菌进入真菌细胞并操纵许可宿主的细胞过程。在拮抗作用中，非宿主真菌的细菌感染是被类似于动植物先天免疫的真菌反应所阻断。在动物和植物中，先天免疫机制防止细菌入侵细胞环境并抑制这些入侵通过启动PCD。为了实现我们揭示毛霉菌先天免疫新机制的目标，我们将使用分离的 EB 作为引发真菌防御反应的工具。我们将测试毛霉菌亚门是否能够：(i) 感知微生物，(iii) 部署防御模块以防止细菌进入，以及 (iii) 面对细菌时能够突破这些主要防御，触发 PCD 消灭入侵者。为了检验这些假设，我们将实现以下具体目标：（1）确定候选先天免疫传感器在非宿主菌株的细菌感染和（2）鉴定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。除了对健康产生深远的影响外，毛霉菌亚门还提供了一个非常方便的研究系统用于阐明多种微生物疾病中真菌-细菌的相互作用。项目预期成果包括确定真菌先天免疫和 PCD 的分子基础，这在未来可能是旨在根除毛霉菌感染。