Establishment of HSV1 latency in immunodeficient mice facilitates efficient in vivo reactivation.
Establishment of HSV1 latency in immunodeficient mice facilitates efficient in vivo reactivation.
复制标题
在免疫缺陷小鼠中建立HSV1潜伏期可有助于体内重新激活。
DOI：
10.1371/journal.ppat.1004730
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Cantin EM
中科院分区：
文献类型：
--
作者：
Ramakrishna C;Ferraioli A;Calle A;Nguyen TK;Openshaw H;Lundberg PS;Lomonte P;Cantin EM
在感觉神经元中潜伏感染的建立是一种非常有效的免疫逃避策略，其解释了人类终身单纯疱疹病毒1型（HSV 1）感染的广泛传播。潜伏病毒的周期性再活化导致HSV 1的无症状脱落和传播或通常为轻度但可为重度的复发性疾病。深入了解调节潜伏期和再激活维持的机制对于开发阻断再激活的新方法至关重要。然而，缺乏一个可靠的小鼠模型，支持有效的体内再激活（IVR），导致生产的感染性HSV 1和/或疾病阻碍了进展。由于HSV 1的再活化增强免疫抑制的主机，我们利用IVIG（静脉注射免疫球蛋白）的抗病毒和免疫调节活性，以促进潜伏感染的免疫缺陷Rag小鼠的生存。高剂量（HD）接种HSV 1后潜伏感染的Rag小鼠表现出自发性再激活，而低剂量（LD）接种则无此现象。高温应激（HS）后，大多数HD接种的小鼠发展HSV 1脑炎（HSE）迅速和同步，而LD接种的小鼠再激活HSV 1持续三叉神经节（Tg）只是短暂的。T细胞，而不是B细胞，需要抑制自发再激活HD接种潜伏感染的小鼠。在HS阻断IVR之前，转移HSV 1记忆而不是OVA特异性或幼稚T细胞，揭示了这种强大的Rag潜伏期模型在研究参与控制再激活的免疫机制中的实用性。将Rag小鼠与各种基因敲除菌株杂交，并用野生型或突变型HSV 1菌株感染它们，预计将为特定细胞和病毒基因在再激活中的作用提供新的见解，从而有助于鉴定具有阻断再激活潜力的新靶点。尽管小鼠模型在HSV 1潜伏期的研究中非常有用，但不能有效地在体内重新激活潜伏的HSV 1阻碍了重新激活的研究。我们推断，在缺乏T细胞的情况下，再活化将更有效，我们利用IVIG来促进缺乏B和T细胞的潜伏感染Rag小鼠的存活。我们建立了一个阈值接种剂量，B6-相比，129-Rag小鼠，这决定了是否可以有效地在体内再激活HSV 1导致脑炎。我们直接表明，记忆T细胞需要控制自发的和诱导的再激活在高剂量接种的小鼠，但在低剂量接种的小鼠维持潜伏期。通过过继细胞转移或杂交将不同的敲除株引入Rag潜伏期模型，将有助于研究参与调节神经元基因表达的各种细胞基因以及先天性和适应性免疫在控制HSV 1再激活中的作用。只有在该领域的研究人员采用和完善之后，这种强大的潜伏期模型才有可能揭示调节潜伏期的分子和免疫机制。
The establishment of latent infections in sensory neurons is a remarkably effective immune evasion strategy that accounts for the widespread dissemination of life long Herpes Simplex Virus type 1 (HSV1) infections in humans. Periodic reactivation of latent virus results in asymptomatic shedding and transmission of HSV1 or recurrent disease that is usually mild but can be severe. An in-depth understanding of the mechanisms regulating the maintenance of latency and reactivation are essential for developing new approaches to block reactivation. However, the lack of a reliable mouse model that supports efficient in vivo reactivation (IVR) resulting in production of infectious HSV1 and/or disease has hampered progress. Since HSV1 reactivation is enhanced in immunosuppressed hosts, we exploited the antiviral and immunomodulatory activities of IVIG (intravenous immunoglobulins) to promote survival of latently infected immunodeficient Rag mice. Latently infected Rag mice derived by high dose (HD), but not low dose (LD), HSV1 inoculation exhibited spontaneous reactivation. Following hyperthermia stress (HS), the majority of HD inoculated mice developed HSV1 encephalitis (HSE) rapidly and synchronously, whereas for LD inoculated mice reactivated HSV1 persisted only transiently in trigeminal ganglia (Tg). T cells, but not B cells, were required to suppress spontaneous reactivation in HD inoculated latently infected mice. Transfer of HSV1 memory but not OVA specific or naïve T cells prior to HS blocked IVR, revealing the utility of this powerful Rag latency model for studying immune mechanisms involved in control of reactivation. Crossing Rag mice to various knockout strains and infecting them with wild type or mutant HSV1 strains is expected to provide novel insights into the role of specific cellular and viral genes in reactivation, thereby facilitating identification of new targets with the potential to block reactivation. Although mouse models have been very useful in studies of HSV1 latency, the inability to efficiently reactivate latent HSV1 in vivo has impeded studies of reactivation. Reasoning that reactivation would be much more efficient in the absence of T cells, we exploited IVIG to promote survival of latently infected Rag mice lacking B and T cells. We established a threshold inoculum dose that was higher for B6- compared to 129-Rag mice, which determined whether HSV1 could be efficiently reactivated in vivo resulting in encephalitis. We showed directly that memory T cells are required to control spontaneous and induced reactivation in mice inoculated at high dose but are dispensable for maintaining latency in low dose inoculated mice. Incorporating different knockout strains into the Rag latency model by adoptive transfer of cells or crossbreeding will facilitate studying the role of various cellular genes involved in regulating neuronal gene expression and innate and adaptive immunity in the control of HSV1 reactivation. The potential of this powerful latency model to unravel the molecular and immune mechanisms regulating latency will be realized only after it is adopted and refined by researchers in the field.
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DOI：
10.1126/science.1164164
发表时间：
2008-10-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Knickelbein JE;Khanna KM;Yee MB;Baty CJ;Kinchington PR;Hendricks RL
通讯作者：
Hendricks RL
DOI：
10.1186/2042-4280-2-5
发表时间：
2011-03-15
期刊：
Herpesviridae
影响因子：
--
作者：
Himmelein S;St Leger AJ;Knickelbein JE;Rowe A;Freeman ML;Hendricks RL
通讯作者：
Hendricks RL
影响因子：
5.4
作者：
Bertke, Andrea S.;Ma, AyeAye;Margolis, Todd P.
通讯作者：
Margolis, Todd P.
影响因子：
5.4
作者：
Cantin, E;Tanamachi, B;Clarke, K
通讯作者：
Clarke, K
影响因子：
7.6
作者：
Frobert, Emilie;Burrel, Sonia;Morfin, Florence
通讯作者：
Morfin, Florence