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Role of macrophages in control of ocular HSV

巨噬细胞在控制眼部 HSV 中的作用

基本信息

批准号：
10222691
负责人：
HOMAYON GHIASI
金额：
$ 41.23万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222691
关键词：
Acute Anterior eyeball segment structure Antiviral Agents Antiviral Response Apoptosis Autophagocytosis Blindness Cells Characteristics Cornea Data Development Disease Dose Exhibits Eye Eye Infections Eye diseases Frequencies Genes Herpetic Keratitis Homeostasis Immune Immune response Immune system Infection Infiltration Inflammation Inflammatory Inflammatory Response Injections Innate Immune Response Kinetics Knockout Mice Lead Leucocytic infiltrate Macrophage Activation Macrophage Colony-Stimulating Factor Maintenance Mediating Mononuclear Mouse Strains Mus Mutate NOS2A gene Natural History Pathway interactions Pattern Phagocytes Phagocytosis Phenotype Plant Roots Play Predisposition Primary Infection Process Publishing Reagent Resolution Role STAT1 gene Simplexvirus Testing Therapeutic Time Tissues Transgenic Mice Tumor-infiltrating immune cells Variant Viral Viral Eye Infections Viral Load result Virus Virus Diseases Virus Latency Virus Replication Vision base clinically relevant clinically significant conditional knockout cytokine in vivo inhibition of autophagy innate immune mechanisms macrophage mouse model mutant novel preservation promoter reactivation from latency recurrent infection response transcription factor

项目摘要

HSV-1 infections are very frequent in the U.S. and are a major cause of viral-induced blindness. The corneal damage induced by HSV-1 appears to be mediated primarily by immune responses. We found that macrophages form early and predominant infiltrates in the corneas of mice ocularly infected with HSV-1. We have also shown that preferential expansion of the M2 macrophage subpopulation by injection of colony stimulating factor-1 (CSF- 1) reduced ocular virus replication and latency-reactivation, whereas activation of the M1 subpopulation was pro- inflammatory and exacerbated eye disease. Analyses of the natural history of very early infiltrates in ocularly infected mice suggest a dichotomy in the patterns of corneal infiltration by M1 and M2 macrophages that is temporally associated with subsequent involvement of other immune responses, clearance of the virus from the cornea, and establishment of latency. These results provide a framework for differentiating immune response- mediated exacerbation vs. immune-mediated control of acute and latent HSV-1 infections. Based on our published and preliminary data, our main hypothesis is that the natural variation in the activation of macrophages towards the M1 or M2 disease-relevant phenotype plays a key role in determining induction of inflammation, eye disease, and virus replication. Therefore, manipulation of M1 and M2 macrophage compartments can be used to safeguard the integrity of the anterior segment of the eye including the cornea in response to infection. Specifically, we will test whether manipulation of autophagy in the macrophage subsets can be used to control ocular HSV-1 infection. The feasibility of the proposed studies is rooted in our strategy that utilizes conditional knockout mice that we have generated to directly evaluate the M1 and M2 functions in vivo with regards to virus replication in the eye, eye disease and establishment of latency-reactivation in ocularly infected mice. We will: (1) Test if altering the phenotype of macrophage activation towards M2 in the cornea of ocularly infected mice will lead to a reduction in primary infection, inflammatory responses and eye disease, and a reduction in latency- reactivation; and (2) Test if inhibition of autophagy in M2 macrophages enhances eye disease and latency- reactivation, while its inhibition in M1 macrophages decreases inflammation, eye disease and latency- reactivation. We will determine the impact of blocking autophagy in transgenic mice expressing the anti- autophagy gene of HSV-1 (i.e., γ34.5) under the M1 (NOS2) or the M2 (Arg1) promoters following infection with WT HSV-1 strain McKrae or a γ34.5 deletion mutant of HSV-1 strain McKrae. In both Aims, we will further test the mechanisms associated with amelioration of the disease process in terms of quantification of antiviral responses, phagocytosis and/or autophagy in the macrophages and the impact on other immune infiltrates and cytokine release.

HSV-1感染在美国非常常见，是病毒性失明的主要原因。角膜 HSV-1诱导的损伤似乎主要由免疫应答介导。我们发现巨噬细胞在眼部感染HSV-1的小鼠角膜中形成早期和主要的浸润。我们还表明通过注射集落刺激因子-1（CSF-CSF），M2巨噬细胞亚群的优先扩增， 1)减少眼部病毒复制和潜伏期再激活，而M1亚群的激活是促增殖的。炎症和加重的眼部疾病。眼部极早期浸润的自然史分析感染的小鼠表明，M1和M2巨噬细胞的角膜浸润模式存在二分法，时间上与随后的其他免疫反应的参与有关，病毒从角膜和潜伏期的建立。这些结果为区分免疫反应提供了一个框架- 介导的急性加重与免疫介导的急性和潜伏HSV-1感染控制。基于我们根据已发表的和初步的数据，我们的主要假设是，巨噬细胞活化的自然变异 M1或M2疾病相关表型在确定炎症诱导、眼内炎症和眼内炎症中起关键作用。疾病和病毒复制。因此，可以使用M1和M2巨噬细胞隔室的操作以保护包括角膜在内的眼前节的完整性，以应对感染。具体来说，我们将测试是否可以使用巨噬细胞亚群中的自噬操作来控制眼部HSV-1感染。建议的研究的可行性是植根于我们的战略，利用条件敲除小鼠，我们已经产生了直接评估M1和M2的功能，在体内关于病毒在眼睛中的复制、眼部疾病和眼部感染小鼠中潜伏期再激活的建立。我们将： (1)测试是否改变眼部感染小鼠角膜中巨噬细胞对M2活化的表型将导致原发性感染、炎症反应和眼部疾病的减少，以及潜伏期的减少- 再激活;和（2）测试M2巨噬细胞中自噬的抑制是否增强眼部疾病和潜伏期- 重新激活，而其在M1巨噬细胞中的抑制作用可减少炎症、眼部疾病和潜伏期- 重新激活我们将确定阻断自噬对表达抗- HSV-1的自噬基因（即，γ34.5）在M1（NOS 2）或M2（Arg 1）启动子下， WT HSV-1菌株McKrae或HSV-1菌株McKrae的γ34.5缺失突变体。在这两个目标中，我们将进一步测试在抗病毒药物的定量方面与疾病过程改善相关的机制巨噬细胞中的免疫应答、吞噬作用和/或自噬作用以及对其他免疫浸润和细胞因子释放

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased phagocytosis in the presence of enhanced M2-like macrophage responses correlates with increased primary and latent HSV-1 infection.

DOI：
10.1371/journal.ppat.1008971
发表时间：
2020-10
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Jaggi U;Yang M;Matundan HH;Hirose S;Shah PK;Sharifi BG;Ghiasi H
通讯作者：
Ghiasi H

Impact of a Demyelination-Inducing Central Nervous System Virus on Expression of Demyelination Genes in Type 2 Lymphoid Cells.

脱髓鞘诱导中枢神经系统病毒对 2 型淋巴细胞脱髓鞘基因表达的影响。

DOI：
10.1128/jvi.01934-20
发表时间：
2021
期刊：
Journal of virology
影响因子：
5.4
作者：
Hirose,Satoshi;Kato,Mihoko;Tormanen,Kati;ShafieiJahani,Pedram;Akbari,Omid;Ghiasi,Homayon
通讯作者：
Ghiasi,Homayon

Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection.

DOI：
10.1371/journal.ppat.1009999
发表时间：
2021-10
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Jaggi U;Matundan HH;Yu J;Hirose S;Mueller M;Wormley FL Jr;Ghiasi H
通讯作者：
Ghiasi H

Deficiency of GATA3-Positive Macrophages Improves Cardiac Function Following Myocardial Infarction or Pressure Overload Hypertrophy.

DOI：
10.1016/j.jacc.2018.05.061
发表时间：
2018-08-21
期刊：
Journal of the American College of Cardiology
影响因子：
24
作者：
Yang M;Song L;Wang L;Yukht A;Ruther H;Li F;Qin M;Ghiasi H;Sharifi BG;Shah PK
通讯作者：
Shah PK

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.