Intact type I Interferon production and IRF7 function in sooty mangabeys.
Intact type I Interferon production and IRF7 function in sooty mangabeys.
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DOI：
10.1371/journal.ppat.1003597
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Silvestri G
中科院分区：
文献类型：
--
作者：
Bosinger SE;Johnson ZP;Folkner KA;Patel N;Hashempour T;Jochems SP;Del Rio Estrada PM;Paiardini M;Lin R;Vanderford TH;Hiscott J;Silvestri G
与人类和恒河猴(RMS)的致病性HIV/SIV感染不同，自然SIV感染Sooty Mangabys(SM)通常是非致病性的，尽管病毒血症很高。一些研究表明，低免疫活性和相对抵抗病毒感染的CD4+中央记忆T细胞是保护手机短信免受艾滋病感染的机制。2008年，有报道称SMS的浆细胞样树突状细胞(PDCs)在体外对TLR7/9配体表现出减弱的干扰素-α(α)反应，而Sm干扰素调节因子-7(IRF7)的物种特异性氨基酸替换导致了这一现象。基于这些发现，这些作者提出，“沉默的”干扰素-α反应是导致短信中SIV感染的良性本质的原因。然而，其他研究表明，急性感染SIV的短信显示出强大的干扰素-α反应和显著的干扰素刺激基因(ISGs)上调。为了研究这种明显的差异，我们首先研究了已报道的IRF7氨基酸替换在SMS中的作用。为此，我们对16个育种者的所有IRF7外显子进行了测序，并在其余群体(177只动物)中对表现出可变性的外显子(外显子2、3、5、6、7、8)进行了测序。我们发现，报道的第191位的Ser-Gly替换是一个测序错误，剩下的几个替换只代表少量等位基因。此外，使用重组SM IRF7进行的功能分析表明，它在细胞核内转位并驱动干扰素-α启动子转录的能力没有缺陷。此外，在体外用TLR7激动剂CL097或SIVmac239刺激SM外周血单核细胞，可诱导pDC产生干扰素-α和干扰素-β，诱导率为500-800倍，而pDC产生的干扰素-α水平与RMS或人相似。这些数据表明，SIV感染的SMS中的干扰素-α和IRF7信号基本完整，与RMS的差异很小，不太可能在SIV感染的SIV感染的SMS的艾滋病抵抗中发挥任何作用。黑猩猩是研究HIV疾病过程的重要模型，因为它们在感染SIV时不会患上艾滋病，SIV是一种灵长类HIV。SIV感染的短信保持健康的原因尚不完全清楚，但与免疫系统的激活减少以及它们关闭强烈的抗病毒反应(干扰素-α)的能力有关，这种反应在感染早期存在，但随着时间的推移而消失。干扰素-α反应是宿主对病毒感染的免疫反应的重要组成部分，但如果它无限期地持续下去，就像感染艾滋病毒的人和易患艾滋病的猕猴那样，可能会导致艾滋病的进展。在这项研究中，我们发现，与先前的报告相反，SMS具有完整的干扰素反应，而SM浆细胞样树突状细胞(PDCs)，一种专门产生干扰素的细胞类型，对SIV的反应并不缺乏。我们还表明，与人类和猕猴相比，IRF7，一种启动干扰素-α反应的必不可少的分子，在短信中维持着功能。这些数据提供了关于SIV感染的SMS如何在病毒水平高的情况下避免艾滋病的新信息，并支持这样的假设，即免疫调节机制奠定了他们快速切断早期感染期间发生的干扰素-α的能力。
In contrast to pathogenic HIV/SIV infections of humans and rhesus macaques (RMs), natural SIV infection of sooty mangabeys (SMs) is typically non-pathogenic despite high viremia. Several studies suggested that low immune activation and relative resistance of CD4+ central memory T-cells from virus infection are mechanisms that protect SMs from AIDS. In 2008 it was reported that plasmacytoid dendritic cells (pDCs) of SMs exhibit attenuated interferon-alpha (IFN-α) responses to TLR7/9 ligands in vitro, and that species-specific amino acid substitutions in SM Interferon Regulatory Factor-7 (IRF7) are responsible for this observation. Based on these findings, these authors proposed that “muted” IFN-α responses are responsible for the benign nature of SIV infection in SMs. However, other studies indicated that acutely SIV-infected SMs show robust IFN-α responses and marked upregulation of Interferon Stimulated Genes (ISGs). To investigate this apparent disparity, we first examined the role of the reported IRF7 amino acid substitutions in SMs. To this end, we sequenced all IRF7 exons in 16 breeders, and exons displaying variability (exons 2,3,5,6,7,8) in the remainder of the colony (177 animals). We found that the reported Ser-Gly substitution at position 191 was a sequencing error, and that several of the remaining substitutions represent only minor alleles. In addition, functional assays using recombinant SM IRF7 showed no defect in its ability to translocate in the nucleus and drive transcription from an IFN-α promoter. Furthermore, in vitro stimulation of SM peripheral blood mononuclear cells with either the TLR7 agonist CL097 or SIVmac239 induced an 500–800-fold induction of IFN-α and IFN-β mRNA, and levels of IFN-α production by pDCs similar to those of RMs or humans. These data establish that IFN-α and IRF7 signaling in SMs are largely intact, with differences with RMs that are minor and unlikely to play any role in the AIDS resistance of SIV-infected SMs. Sooty mangabey (SM) monkeys are an important model for studying HIV disease processes because they do not develop AIDS when infected with SIV, a primate version of HIV. The reasons why SIV-infected SMs remain healthy are not completely understood, but are related to reduced activation of the immune system, and to their ability to shut off a strong antiviral response (Interferon-alpha), that is present during early infection but disappears over time. The interferon-alpha response is an essential component of the host immune response to viral infections, but may contribute to AIDS progression if it persists indefinitely, as occurs in HIV-infected humans and AIDS-susceptible macaque monkeys. In this study, we found that, contrary to a previous report, SMs had an intact interferon response, and SM plasmacytoid dendritic cells (pDCs), a cell-type specialized in producing interferon, were not deficient in their responses to SIV. We also show that IRF7, a molecule essential to initiate the interferon-alpha response, maintains function in SMs compared to humans and macaques. These data provide novel information on how SIV-infected SMs avoid AIDS despite high levels of virus, and support the hypothesis that immuno-regulatory mechanisms underlie their ability to rapidly shut-off the interferon-alpha that occurs during early infection.
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