Exploration of immunological responses underpinning severe fever with thrombocytopenia syndrome virus infection reveals IL-6 as a therapeutic target in an immunocompromised mouse model.
Exploration of immunological responses underpinning severe fever with thrombocytopenia syndrome virus infection reveals IL-6 as a therapeutic target in an immunocompromised mouse model.
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DOI：
10.1093/pnasnexus/pgac024
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Brennan, Benjamin
中科院分区：
文献类型：
--
作者：
Bryden, Steven R.;Dunlop, James I.;Clarke, Andrew T.;Fares, Mazigh;Pingen, Marieke;Wu, Yan;Willett, Brian J.;Patel, Arvind H.;Gao, George F.;Kohl, Alain;Brennan, Benjamin
大别班达病毒（以前称为严重发热伴血小板减少综合征病毒；SFTSV）是一种新出现的蜱传布尼亚病毒，可引起严重发热伴血小板减少综合征（SFTS），这是一种病死率高的疾病，其特征是高热、血小板减少和潜在致命的出血表现。目前，既没有有效的治疗策略，也没有批准的疫苗。因此，迫切需要更好地了解该疾病的发病机制，并确定改善SFTS结果的治疗策略。使用I型干扰素（IFN）缺陷小鼠模型，我们研究了病毒的趋向性、疾病动力学以及毒力因子非结构蛋白（NSs）在SFTS中的作用。淋巴组织中的Ly6C+ MHCII+细胞被确定为SFTSV的重要靶细胞。晚期SFTS的特征是炎性白细胞（尤其是中性粒细胞）显著迁移到淋巴结和脾脏，然而，这些细胞并不需要协调疾病表型。SFTS的发生与促炎细胞因子的显著上调有关，包括血清、淋巴结和脾脏中高水平的IFN-γ和IL-6。接种delNSs SFTSV产生的体液免疫具有100%的保护性。重要的是，NSs对抑制宿主IFN α反应或下游IFN刺激的基因产生至关重要，并允许严重疾病的建立。最后，治疗性而非预防性使用抗il -6抗体可显著提高SFTSV感染后小鼠的存活率，因此，这种治疗方式为治疗严重SFTS提供了一种新的治疗策略。
Dabie bandavirus (previously severe fever with thrombocytopenia syndrome virus; SFTSV), is an emerging tick-borne bunyavirus responsible for severe fever with thrombocytopenia syndrome (SFTS), a disease with high case fatality that is characterized by high fever, thrombocytopenia, and potentially lethal hemorrhagic manifestations. Currently, neither effective therapeutic strategies nor approved vaccines exist for SFTS. Therefore, there remains a pressing need to better understand the pathogenesis of the disease and to identify therapeutic strategies to ameliorate SFTS outcomes. Using a type I interferon (IFN)-deficient mouse model, we investigated the viral tropism, disease kinetics, and the role of the virulence factor nonstructural protein (NSs) in SFTS. Ly6C+ MHCII+ cells in the lymphatic tissues were identified as an important target cell for SFTSV. Advanced SFTS was characterized by significant migration of inflammatory leukocytes, notably neutrophils, into the lymph node and spleen, however, these cells were not required to orchestrate the disease phenotype. The development of SFTS was associated with significant upregulation of proinflammatory cytokines, including high levels of IFN-γ and IL-6 in the serum, lymph node, and spleen. Humoral immunity generated by inoculation with delNSs SFTSV was 100% protective. Importantly, NSs was critical to the inhibition of the host IFNɣ response or downstream IFN-stimulated gene production and allowed for the establishment of severe disease. Finally, therapeutic but not prophylactic use of anti-IL-6 antibodies significantly increased the survival of mice following SFTSV infection and, therefore, this treatment modality presents a novel therapeutic strategy for treating severe SFTS.
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DOI：
10.1016/j.jcv.2018.01.017
发表时间：
2018-04
期刊：
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
影响因子：
--
作者：
Kwon JS;Kim MC;Kim JY;Jeon NY;Ryu BH;Hong J;Kim MJ;Chong YP;Lee SO;Choi SH;Kim YS;Woo JH;Kim SH
通讯作者：
Kim SH
影响因子：
6
作者：
Muralidharan A;Reid SP
通讯作者：
Reid SP
新兴tick传播静脉病毒的动物模型：在SFTSV感染的致命模型中确定靶细胞。
影响因子：
5.2
作者：
Matsuno K;Orba Y;Maede-White K;Scott D;Feldmann F;Liang M;Ebihara H
通讯作者：
Ebihara H
影响因子：
8.1
作者：
Hojyo S;Uchida M;Tanaka K;Hasebe R;Tanaka Y;Murakami M;Hirano T
通讯作者：
Hirano T
DOI：
10.4049/jimmunol.1200385
发表时间：
2012-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Griffin GK;Newton G;Tarrio ML;Bu DX;Maganto-Garcia E;Azcutia V;Alcaide P;Grabie N;Luscinskas FW;Croce KJ;Lichtman AH
通讯作者：
Lichtman AH