Zika virus induced microcephaly and aberrant hematopoietic cell differentiation modeled in novel neonatal humanized mice.
Zika virus induced microcephaly and aberrant hematopoietic cell differentiation modeled in novel neonatal humanized mice.
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DOI：
10.3389/fimmu.2023.1060959
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发表时间：
2023
影响因子：
7.3
通讯作者：
Akkina R
中科院分区：
文献类型：
--
作者：
Schmitt K;Curlin JZ;Remling-Mulder L;Aboellail T;Akkina R
免疫功能正常和免疫功能低下的小鼠模型有助于回答有关寨卡病毒发病机制和垂直传播的重要问题。然而，在这些小鼠模型中模拟人类先天性寨卡综合征（CZS）特征并不是最佳的，并且不能解决病毒对人类免疫系统的潜在影响。在此，我们利用新生人源化Rag2-/-γc-/-小鼠来模拟cz，并在体内评估病毒对人造血干细胞分化的潜在影响。将新生Rag2-/-γ - c-/-小鼠植入感染zikv的造血干细胞（HSC），并监测其症状和病变。13天内，小鼠表现出生长发育迟缓、驼背、毛发皱褶和眼部缺陷等外在临床症状。大脑和内脏器官的明显病理被注意到。我们的研究结果也证实了ZIKV积极感染人CD34+造血干细胞并限制终分化B细胞的发育。组织学上，在大脑的几个不同区域存在多灶矿化，并伴有寨卡病毒抗原共定位。锥体神经元弥漫性坏死，海马结构塌陷。总的来说，该模型概括了寨卡病毒小头畸形和CZS以及病毒对人类免疫细胞个体发育的不良影响，从而提供了一个独特的体内模型来评估新疗法和免疫干预的疗效。
Immunocompetent and immunocompromised murine models have been instrumental in answering important questions regarding ZIKV pathogenesis and vertical transmission. However, mimicking human congenital zika syndrome (CZS) characteristics in these murine models has been less than optimal and does not address the potential viral effects on the human immune system. Here, we utilized neonatal humanized Rag2-/-γc-/- mice to model CZS and evaluate the potential viral effects on the differentiation of human hematopoietic stem cells in vivo. Newborn Rag2-/-γc-/- mice were engrafted with ZIKV-infected hematopoietic stem cells (HSC) and monitored for symptoms and lesions. Within 13 days, mice displayed outward clinical symptoms that encompassed stunted growth, hunched posture, ruffled fur, and ocular defects. Striking gross pathologies in the brain and visceral organs were noted. Our results also confirmed that ZIKV actively infected human CD34+ hematopoietic stem cells and restricted the development of terminally differentiated B cells. Histologically, there was multifocal mineralization in several different regions of the brain together with ZIKV antigen co-localization. Diffuse necrosis of pyramidal neurons was seen with collapse of the hippocampal formation. Overall, this model recapitulated ZIKV microcephaly and CZS together with viral adverse effects on the human immune cell ontogeny thus providing a unique in vivo model to assess the efficacy of novel therapeutics and immune interventions.
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影响因子：
3.8
作者：
Dowall SD;Graham VA;Rayner E;Atkinson B;Hall G;Watson RJ;Bosworth A;Bonney LC;Kitchen S;Hewson R
通讯作者：
Hewson R
DOI：
10.1056/nejmoa1602412
发表时间：
2016-12-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brasil P;Pereira JP Jr;Moreira ME;Ribeiro Nogueira RM;Damasceno L;Wakimoto M;Rabello RS;Valderramos SG;Halai UA;Salles TS;Zin AA;Horovitz D;Daltro P;Boechat M;Raja Gabaglia C;Carvalho de Sequeira P;Pilotto JH;Medialdea-Carrera R;Cotrim da Cunha D;Abreu de Carvalho LM;Pone M;Machado Siqueira A;Calvet GA;Rodrigues Baião AE;Neves ES;Nassar de Carvalho PR;Hasue RH;Marschik PB;Einspieler C;Janzen C;Cherry JD;Bispo de Filippis AM;Nielsen-Saines K
通讯作者：
Nielsen-Saines K
影响因子：
3.7
作者：
Akkina R
通讯作者：
Akkina R
影响因子：
28.3
作者：
Foo SS;Chen W;Chan Y;Bowman JW;Chang LC;Choi Y;Yoo JS;Ge J;Cheng G;Bonnin A;Nielsen-Saines K;Brasil P;Jung JU
通讯作者：
Jung JU
影响因子：
4.6
作者：
Julander JG;Siddharthan V;Park AH;Preston E;Mathur P;Bertolio M;Wang H;Zukor K;Van Wettere AJ;Sinex DG;Morrey JD
通讯作者：
Morrey JD