T cell-dependence of Lassa fever pathogenesis.
T cell-dependence of Lassa fever pathogenesis.
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DOI：
10.1371/journal.ppat.1000836
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发表时间：
2010-03-26
期刊：
影响因子：
6.7
通讯作者：
Pinschewer DD
中科院分区：
文献类型：
--
作者：
Flatz L;Rieger T;Merkler D;Bergthaler A;Regen T;Schedensack M;Bestmann L;Verschoor A;Kreutzfeldt M;Brück W;Hanisch UK;Günther S;Pinschewer DD
拉沙病毒（LASV）是拉沙热（LF）的病原体，在西非流行，占相当大的发病率和死亡率。尽管正在进行的研究工作，LF发病机制和LASV免疫控制机制仍然知之甚少。虽然正常的实验室小鼠对LASV有抵抗力，但我们报告表达人源化而不是鼠I类MHC（MHC-I）的小鼠未能控制LASV感染并发生严重的LF。MHC-I基因敲除小鼠的感染证实了MHC-I限制性T细胞应答在控制LASV中的关键作用。有趣的是，我们发现LASV感染的HHD小鼠的T细胞耗竭可以预防疾病，而不管是否存在高水平的病毒血症。单核细胞/巨噬细胞谱系细胞的广泛活化（通过诱导型NO合酶表达而显现）和升高的IL-12 p40血清水平指示全身性炎症状况。在T细胞耗竭小鼠中不存在广泛的单核细胞/巨噬细胞活化，表明T细胞应答有助于有害的先天性炎症反应和LF发病机制。我们在小鼠中的观察表明T细胞的双重作用，不仅保护免受LASV，而且增强LF发病机制。T细胞驱动的增强和免疫发病机制的可能性，应考虑在未来的LF疫苗的发展。拉沙病毒（LASV）是拉沙热（LF）的病原体，是西非发病率和死亡率很高的原因。然而，导致疾病的机制仍然知之甚少。在这里，我们提出了一个概念，即人体的免疫防御要么迅速击败LASV，或者，如果不成功，成为一个重要的促进疾病。后一个自相矛盾的假设源于对基因工程（HHD）小鼠的观察，我们发现这些小鼠对LF易感。HHD小鼠与抗性野生型小鼠的不同之处在于它们具有人源化的T细胞库，T细胞是哺乳动物免疫系统的主要组成部分。与直觉相反，我们可以通过实验性地去除HHD小鼠的T细胞来保护它们免受LF的侵害。我们进一步发现LF与巨噬细胞的广泛激活相关，巨噬细胞再次依赖于T细胞。与T细胞类似，巨噬细胞是我们身体防御系统的重要参与者，但它们的炎症产物也是LF的候选介质。两者合计，这些研究结果表明，LF可能代表一个不适当的主机对感染的反应。具体而言，我们的研究表明了T细胞对LASV的反应具有两面性。在未来的LF疫苗开发中需要考虑免疫防御的这些有害方面，以避免在接种疫苗的个体中增强疾病。
Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development. Lassa virus (LASV) is the causative agent of Lassa fever (LF), accounting for substantial morbidity and mortality in West Africa. Yet the mechanisms leading to disease remain poorly understood. Here we propose a concept whereby the body's immune defense either defeats LASV rapidly or, if unsuccessful, becomes an essential facilitator of disease. This latter paradoxical postulate stems from observations in genetically engineered (HHD) mice, which we found to be susceptible to LF. HHD mice differ from resistant wild type mice in that they have a humanized repertoire of T cells, a main component of the mammalian immune system. Counterintuitively, we could protect HHD mice against LF by experimentally removing their T cells. We further found that LF correlated with widespread activation of macrophages, which again depended on T cells. Similar to T cells, macrophages are important players in our body's defense system, but their inflammatory products are also candidate mediators of LF. Taken together, these findings suggest that LF may represent an inappropriate host response to infection. Specifically, our study demonstrates a two-faced role of T cell responses against LASV. Such detrimental aspects of immune defense need to be given consideration in future LF vaccine development, to avoid enhancement of disease in vaccinated individuals.
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DOI：
10.4269/ajtmh.1970.19.670
发表时间：
1970-01-01
影响因子：
3.3
作者：
FRAME, JD;BALDWIN, JM;TROUP, JM
通讯作者：
TROUP, JM
影响因子：
5.4
作者：
JAHRLING, PB;PETERS, CJ
通讯作者：
PETERS, CJ
DOI：
10.1084/jem.20070784
发表时间：
2007-10-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Almeida JR;Price DA;Papagno L;Arkoub ZA;Sauce D;Bornstein E;Asher TE;Samri A;Schnuriger A;Theodorou I;Costagliola D;Rouzioux C;Agut H;Marcelin AG;Douek D;Autran B;Appay V
通讯作者：
Appay V
影响因子：
5.4
作者：
Asper, M;Sternsdorf, T;Günther, S
通讯作者：
Günther, S
影响因子：
5.4
作者：
Botten, Jason;Alexander, Jeff;Buchmeier, Michael J.
通讯作者：
Buchmeier, Michael J.