Role of macrophages in control of ocular HSV

巨噬细胞在控制眼部 HSV 中的作用

• 批准号: 9144799
• 负责人: HOMAYON GHIASI
• 金额: $ 43.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144799
• 关键词: Acute; Adjuvant; Antibodies; Antigen Presentation; Blindness; Cells; Chronic; Cornea; Corneal Diseases; DNA; Developed Countries; Disease; Exhibits; Eye; Eye Infections; Eye diseases; Generations; Genes; Herpesvirus 1; Herpetic Keratitis; Hour; ITGAM gene; Immune; Immune response; Immune system; Immunization; Infection; Infectious Agent; Injection of therapeutic agent; Interferon Type II; Interferons; Interleukin-2; Interleukin-4; Keratitis; Lead; Macrophage Colony-Stimulating Factor; Molecular; Mus; Natural Immunity; PPBP gene; Pathology; Phagocytosis; Play; Prevention; Recombinants; Recurrence; Reporting; Role; Simplexvirus; Structure of trigeminal ganglion; System; Testing; Tissues; Vaccination; Viral; Viral Load result; Viral load measurement; Virus; Virus Diseases; Virus Latency; Virus Replication; chemokine; corneal scar; cytokine; cytotoxicity; improved; macrophage; prevent; public health relevance; reactivation from latency; recombinant virus; response; therapeutic vaccine; tumor

 DESCRIPTION (provided by applicant): Macrophage infiltrates play a variety of key roles in the immune defense system, including a central role in innate or natural immunity. We have shown by immunostaining using anti-F4/80 and CD11b antibodies that resident corneal macrophages are not detectable in cornea of uninfected mice. In contrast, following infection of mice with herpes simplex virus type-1 (HSV-1), macrophages appear to be the most dominant infiltrate of the eye. Thus, macrophages may play a central role in both exacerbation and control of acute and chronic HSV-1 infection. In line with our previous studies, our Preliminary studies also suggest that: 1. Injection of mice with macrophage-colony stimulating factor (M-CSF) DNA reduced virus replication in the eye and establishment of latency in trigeminal ganglia (TG) of ocularly infected mice. 2. Similar to M-CSF injection, injection of mice with IL-12p35 DNA also reduced virus replication in the eye and establishment of latency in TGs of latently infected mice. Thus, since macrophages are the most abundant infiltrates in the eye of HSV-1 ocularly infected mice and also appear the fastest in the eye (as early as 4 hours) after ocular infection, we will use macrophage stimulatory factors (i.e., M-CSF and IL-12p35) to reduce virus replication in the eye and establishment of latency in the TGs of ocularly infected mice. We propose to: Aim: Test the hypothesis that macrophage stimulation by a combination of IL-12p35 and M-CSF DNA as molecular adjuvants will enhance TH1/TC1 responses in the eye and lead to a more rapid clearance of virus from the eye and trigeminal ganglia (TG) during primary ocular HSV-1 infection. This will, lead to a significant reduction in establishment of latency and reactivation in TG of latently infected mice. Our preliminary studies suggest that administration of IL-12p35 and M-CSF DNA improves immunization efficacy as judged by a greater reduction in virus replication in the eye after ocular infection compare with control mice, or mice that are immunized with IL-12p35 or M-CSF alone. This improved efficacy correlated with higher activities of local ocular responses (i.e., IL-2, IFN-a, IFN-ß, IFN- γ). We propose to test the hypothesis that; (1) a cocktail of IL-12p35 and M-CSF DNA will result in reduction in primary virus replication in the eyes as well as reduction of latency in TGs of infected mice; (2) these reductions are associated with generation of strong and rapid TH1/TC1 responses in addition to IFN-a and IFN-ß in the eye and TGs of infected mice; and (3) Co-administration of IL-12p35 + M-CSF + 5gP DNA will further reduce latency in immunized mice compared with mice that treated with 5gP alone. Overall, we expect to determine that a combination of IL-12p35 and M-CSF enhances the cytokine secretion and antigen presentation functions of macrophages rather than their phagocytosis function.

 描述（由申请人提供）：巨噬细胞浸润在免疫防御系统中发挥着多种关键作用，包括在先天或自然免疫中的核心作用。我们通过使用抗 F4/80 和 CD11b 抗体的免疫染色表明，驻留角膜巨噬细胞是。相比之下，在感染 1 型单纯疱疹病毒 (HSV-1) 的小鼠中，巨噬细胞似乎最多。因此，巨噬细胞可能在急性和慢性 HSV-1 感染的恶化和控制中发挥核心作用，我们的初步研究还表明： 1. 向小鼠注射巨噬细胞。集落刺激因子 (M-CSF) DNA 减少了眼部感染小鼠眼中的病毒复制和三叉神经节 (TG) 潜伏期的建立。 2. 与 M-CSF 注射类似，给小鼠注射IL-12p35 DNA 还减少了病毒在眼睛中的复制和潜伏感染小鼠 TG 中潜伏期的建立，因此，由于巨噬细胞是 HSV-1 眼部感染小鼠眼睛中最丰富的浸润细胞，并且在眼睛中出现最快。眼部感染后最早 4 小时），我们将使用巨噬细胞刺激因子（即 M-CSF 和 IL-12p35）来减少眼部病毒复制并建立潜伏期。我们建议： 目的：测试这样的假设：IL-12p35 和 M-CSF DNA 组合作为分子佐剂刺激巨噬细胞将增强眼睛中的 TH1/TC1 反应并导致更快的清除。在原发性眼 HSV-1 感染期间，病毒从眼和三叉神经节 (TG) 中排出，这将导致潜伏感染小鼠 TG 的潜伏期建立和重新激活显着减少。我们的初步研究表明，与对照小鼠或用 IL-12p35 或 M-CSF 免疫的小鼠相比，施用 IL-12p35 和 M-CSF DNA 可提高免疫效果，这是通过眼部感染后眼内病毒复制的更大减少来判断的。单独使用脑脊液。这种疗效的提高与局部眼部反应（即 IL-2、IFN-α、IFN-β、IFN-γ）的较高活性相关。我们建议检验以下假设： IL-12p35 和 M-CSF DNA 的混合物将导致原代病毒在眼睛中的复制减少以及受感染小鼠 TG 潜伏期的减少；(2) 这些减少与强而快速的 TH1/TC1 的产生有关；除了 IFN-a 和 IFN-ß 之外，感染小鼠的眼睛和 TG 也有反应；(3) 联合施用 IL-12p35 + M-CSF + 5gP DNA 将进一步减少感染小鼠的潜伏期。总体而言，我们期望确定 IL-12p35 和 M-CSF 的组合增强巨噬细胞的细胞因子分泌和抗原呈递功能，而不是吞噬功能。