Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection.
Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection.
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DOI：
10.7554/elife.04494
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发表时间：
2015-01-20
期刊：
影响因子：
7.7
通讯作者：
Virgin HW
中科院分区：
文献类型：
--
作者：
MacDuff DA;Reese TA;Kimmey JM;Weiss LA;Song C;Zhang X;Kambal A;Duan E;Carrero JA;Boisson B;Laplantine E;Israel A;Picard C;Colonna M;Edelson BT;Sibley LD;Stallings CL;Casanova JL;Iwai K;Virgin HW
遗传性免疫缺陷症表现的变异可由遗传或环境因素解释。HOIL 1（RBCK 1）突变的患者表现为支链淀粉病相关肌病，伴或不伴过度炎症和免疫缺陷。我们报道了屏障升高HOIL-1缺陷小鼠在心肌中表现出支链淀粉样沉积，但表现出极轻微的过度炎症迹象。然而，它们在急性感染单核细胞增生李斯特菌、刚地弓形虫或啮齿柠檬酸杆菌时表现出免疫缺陷。对李斯特菌的易感性增加是由于HOIL-1在造血细胞和巨噬细胞中产生保护性细胞因子的功能。相比之下，HOIL-1缺陷小鼠对慢性结核分枝杆菌或鼠γ-疱疹病毒68（MHV 68）的控制增强，这些感染赋予了高度炎症表型。令人惊讶的是，MHV 68的慢性感染补充了李斯特菌感染后HOIL-1、IL-6、Caspase-1和Caspase-1; Caspase-11缺陷小鼠的免疫缺陷。因此，慢性疱疹病毒感染产生自身炎症的迹象，并补充突变小鼠的遗传免疫缺陷，突出了在基因型-表型研究中考虑病毒组的重要性。DOI：www.example.com免疫系统保护个体免受入侵的细菌、病毒和寄生虫，以及功能失常或癌变的宿主细胞。然而，有些人遗传了导致部分免疫系统缺失或无法正常工作的遗传缺陷。这被称为遗传性免疫缺陷，并使个体处于感染和疾病的更高风险中。免疫缺陷的症状可以在个体之间有很大差异，即使他们在同一基因中有缺陷。例如，据报道，只有一些在两个称为HOIL-1的基因拷贝中都有缺陷的个体才对细菌感染和慢性（持续性）炎症的易感性发生改变。HOIL-1与人体免疫反应中的几个角色有关。对影响遗传免疫缺陷症状变化的可能因素有一个清楚的了解，可以帮助加快诊断速度，并帮助开发更有效的治疗方法。MacDuff等人研究了HOIL-1基因的小鼠等价物的两个拷贝都有突变的小鼠。这些小鼠在一个清洁的屏障设施中长大，减少了它们对病毒的接触，严重免疫缺陷，并在感染某些细菌和寄生虫（包括单核细胞增生李斯特菌）时死亡。然而，他们能够忍受疱疹病毒或导致肺结核的细菌的感染。对L.单核细胞增多症与产生称为细胞因子的保护性分子的问题有关，细胞因子是免疫反应的关键部分。出乎意料的是，MacDuff等人发现，慢性疱疹病毒感染基本上保护了这些非常免疫缺陷的动物免受单核细胞增生李斯特菌感染，并且小鼠能够有效地产生保护性细胞因子。另外两种影响免疫系统的不同遗传缺陷的小鼠，如果长期感染疱疹病毒，也能更好地在致命的细菌感染中存活。Macduff等人认为，慢性疱疹病毒感染刺激免疫系统，因此使其能够补偿与各种免疫缺陷相关的细胞因子产生的缺乏，包括由HOIL-1基因突变引起的免疫缺陷。这表明，病毒或其他长期感染的存在可能是导致具有相同遗传免疫缺陷的不同个体的症状中所见的一些变异性的原因。这是一个重要的概念，因为基本上所有人都有各种疱疹病毒以及形成人类病毒组的其他病毒的终身慢性感染。DOI：www.example.com网站
Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies. DOI: http://dx.doi.org/10.7554/eLife.04494.001 The immune system protects an individual from invading bacteria, viruses and parasites, as well as malfunctioning or cancerous host cells. However, some people inherit genetic defects that cause part of the immune system to be missing or to not work properly. This is called a genetic immunodeficiency, and puts individuals at a higher risk of infection and disease. The symptoms of immunodeficiencies can vary substantially between individuals, even when they have defects in the same gene. For example, only some of the individuals who have defects in both of their copies of a gene called HOIL-1—which has been linked to several roles in the body's immune response—are reported to suffer from an altered susceptibility to bacterial infections and chronic (persistent) inflammation. Gaining a clear understanding of the possible factors that influence such variations in the symptoms of genetic immune deficiencies could help to speed up their diagnosis, as well as helping to develop more effective treatments. MacDuff et al. studied mice that had mutations in both copies of the mouse equivalent of the HOIL-1 gene. These mice, when raised in a clean barrier facility that reduces their exposure to viruses, were severely immunodeficient and died when infected by certain bacteria and parasites, including Listeria monocytogenes. However, they were able to tolerate infections with a herpesvirus or the bacterium that causes tuberculosis. The immunodeficiency to L. monocytogenes was linked to problems producing protective molecules called cytokines, which form a crucial part of the immune response. Unexpectedly, MacDuff et al. found that a chronic herpesvirus infection substantially protected these very immunodeficient animals from infection with Listeria monocytogenes, and the mice were able to efficiently produce protective cytokines. Mice with two other distinct genetic deficiencies that affect their immune system were also better able to survive otherwise lethal bacterial infections if they had a long-term herpesvirus infection. Macduff et al. suggest that the chronic herpesvirus infection stimulates the immune system, and so allows it to compensate for the lack of cytokine production associated with various immunodeficiencies, including those caused by mutations in the HOIL-1 gene. This suggests that the presence of viruses or other long-term infections may be responsible for some of the variability seen in the symptoms of different individuals with the same genetic immunodeficiency. This is an important concept since essentially all humans have life-long chronic infections from various herpesviruses, as well as other viruses that form the human virome. DOI: http://dx.doi.org/10.7554/eLife.04494.002