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Modulation of Human Cells by Virulent Francisella tularensis

有毒土拉弗朗西斯菌对人体细胞的调节

基本信息

批准号：
10927845
负责人：
Catharine Bosio
金额：
$ 35.65万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10927845
关键词：
Acellular Vaccines Acute Aerosols Anti-Inflammatory Agents Bacteria Bacterial Infections Carbohydrates Cells Dangerousness Data Defect Dendritic Cells Dengue Virus Development Disease Francisella Francisella tularensis Goals Health Human Immune response Immune system Immunosuppression Impairment In Vitro Incubated Individual Infection Infectious Agent Inflammation Inflammatory Inflammatory Response Inhalation Invaded Laboratories Legal patent Lipid Synthesis Pathway Lipids Liposomes Macrophage Mediating Membrane Metabolic Metabolic Pathway Metabolism Microbe Mus Natural Immunity O Antigens Pathogenicity Play Predisposition Proteins Pulmonary tularemia Research Role Route Secondary to Sentinel Signal Pathway Signaling Molecule Stimulus Structure Surface Symptoms Testing Therapeutic Time Tularemia USSR United States Virulence Virulent adaptive immunity bioweapon capsule carbohydrate structure cell killing cytokine in vivo mortality mutant novel novel therapeutics novel vaccines pathogen pathogenic bacteria prevent programs receptor response transmission process vector-borne weapons

项目摘要

Francisella tularensis (FT), the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, it is inhalation of the bacterium, and the resulting pneumonic tularemia, that represents the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%) in untreated individuals. Furthermore, FT has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on FT around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection. My laboratory has established that, similarly to murine cells, human dendritic cells and macrophages are acutely susceptible to infection with FT, but fail to produce pro-inflammatory cytokines or undergo maturation. Further, virulent FT actively interferes with the ability of human DC and macrophages to respond to secondary stimuli. Understanding the mechanism by which FT actively suppresses DC and macrophage function is a central directive of my laboratory. We are tackling this directive in two different ways. Specific Aim 1: We are analyzing the role Francisella lipids play in mediating anti-inflammatory responses. Structures present on the surface of bacteria are the first components encountered by the host cell. Thus, it is possible that, in the context of FT infections, these structures contribute to the early, rapid suppression of human dendritic cells. Bacterial lipids represent one such structure. We have recently identified one of the active lipid species present in FT that inhibit inflammation. We have tested a synthetic version of this lipid and confirmed that it also impairs inflammatory responses. We have identified one of the receptors utilized by both the intact bacterium and purified lipid as well as a host signaling molecule required to promote immunosuppressive responses. Importantly, we have also demonstrated that FT lipids can limit pathogenic inflammatory responses driven by other infectious agents in vitro, including Dengue virus. We have screened FT lipids (including synthetic liposomes) for off target effects in vivo following delivery via multiple routes and have also found that they potently dampen inflammation driven by unrelated bacterial infection in vivo. We have filed a patent application for use of FT lipids as novel anti-inflammatory therapeutics. We are currently identifying the other lipids present in FT that contribute to suppression of inflammation and additional mechanisms by which they interfere with functions in human cell. We have generated a lipid mutant and identified a requirement for a specific species of FT lipid in evasion, but not suppression, of pro-inflammatory responses in human cells. Additionally, we are examining the contribution of host lipid synthesis pathways following infection with F. tularensis. Specific Aim 2: We are exploring the role of carbohydrates associated with the outer surface of FT in directing immunosuppressive programs in human cells. The major outer surface carbohydrate structure of FT is the O-Antigen (O-Ag) capsule. Typically, capsules are thought to simply cover up proteins present on the bacterial surface that could stimulate an inflammatory response. However, our data demonstrates that FT capsule directly inhibits pro-inflammatory responses in human cells. Further, we have demonstrated that capsule influences specific metabolic pathways in the host the modulate cell health and inflammatory responses. Utilizing mutants with specific defects in capsule synthesis along with purified FT capsule, we are currently identifying the specific receptors and host signaling pathways modulated by capsule to initiate an anti-inflammatory program inhuman cells.

土拉菌弗朗西斯菌（FT）是土拉菌病的病原体，可通过多种途径感染人类，包括媒介传播。然而，吸入这种细菌以及由此产生的肺炎土拉菌病是最危险的一种疾病。这是由于潜伏期短（3-5天）、非特异性症状和未经治疗个体的高死亡率（大于80%）。此外，美国和前苏联都已将其武器化，使其成为生物武器的可行候选。尽管全球对FT进行了80多年的研究，但人们对这种细菌与宿主的动态相互作用知之甚少，尤其是在气溶胶感染之后。