Division of Pathology, ICAR-Indian Veterinary Research Institute (ICAR-IVRI), Izatnagar, Bareilly 243122, Uttar Pradesh, India.
ICAR-National Institute of Veterinary Epidemiology and Disease Informatics, Bengaluru 560064, Karnataka, India.
J Adv Res. 2021 Jan 20;31:137-153. doi: 10.1016/j.jare.2021.01.007. eCollection 2021 Jul.
Wild-type adult mice with intact interferon (IFN) system were neither susceptible to bluetongue virus (BTV) infection nor showed signs of morbidity/mortality. Establishment of immunologically competent wild-type adult mouse model with type I IFNs blockade is necessary to assess the pathogenesis, immune responses and testing of BTV vaccines.
Present study aimed to establish and characterize BTV serotype 1 infection in immunocompetent adult mice with type I IFNs blockade at the time of infection by studying immune responses and sequential pathology.
Adult mice were administered with anti-mouse IFN-α/β receptor subunit-1 (IFNAR1) blocking antibody (Clone: MAR1-5A3) 24 h before and after BTV serotype 1 infection, and sacrificed at various time points. Sequential pathology, BTV localization by immunohistochemistry and quantification by qRT-PCR, immune cell kinetics and apoptosis by flow cytometry, and cytokines estimation by c-ELISA and qRT-PCR were studied.
IFNAR blocked-infected mice developed clinical signs and typical lesions of BT; whereas, isotype-infected control mice did not develop any disease. The IFNAR blocked-infected mice showed enlarged, edematous, and congested lymph nodes (LNs) and spleen, and vascular (congestion and hemorrhage) and pneumonic lesions in lungs. Histopathologically, marked lymphoid depletion with "starry-sky pattern" due to lymphocytes apoptosis was noticed in the LNs and spleen. BTV antigen was detected and quantified in lymphoid organs, lungs, and other organs at various time points. Initial leukopenia (increased CD4/CD8 T cells ratio) followed by leukocytosis (decreased CD4/CD8 T cells ratio) and significantly increased biochemical values were noticed in IFNAR blocked-infected mice. Increased apoptotic cells in PBMCs and tissues coincided with viral load and levels of different cytokines in blood, spleen and draining LNs and notably varied between time points in IFNAR blocked-infected mice.
Present study is first to characterize BTV serotype 1 infection in immunocompetent adult mouse with type I IFNs blockade. The findings will be useful for studying pathogenesis and testing the efficacy of BTV vaccines.
野生型成年小鼠的干扰素（IFN）系统完整，既不易感染蓝舌病毒（BTV），也无发病或死亡迹象。建立 I 型 IFN 阻断的免疫功能正常成年小鼠模型对于评估 BTV 疫苗的发病机制、免疫反应和测试是必要的。
本研究旨在通过研究免疫反应和连续病理学，建立并描述 I 型 IFN 阻断时免疫功能正常的成年小鼠感染 BTV 血清型 1 的情况。
成年小鼠在 BTV 血清型 1 感染前 24 小时和感染后 24 小时给予抗鼠 IFN-α/β受体亚基-1（IFNAR1）阻断抗体（克隆：MAR1-5A3），并在不同时间点处死。研究连续病理学、免疫组化定位 BTV 和 qRT-PCR 定量、通过流式细胞术研究免疫细胞动力学和细胞凋亡、c-ELISA 和 qRT-PCR 测定细胞因子。
IFNAR 阻断感染的小鼠出现了 BT 的临床症状和典型病变；而同种型感染对照小鼠未出现任何疾病。IFNAR 阻断感染的小鼠表现出增大、水肿和充血的淋巴结（LN）和脾脏，以及肺部的血管（充血和出血）和肺炎病变。组织病理学上，在 LN 和脾脏中观察到由于淋巴细胞凋亡导致的明显淋巴细胞耗竭和“星空模式”。在不同时间点在淋巴器官、肺部和其他器官中检测到 BTV 抗原并进行定量。IFNAR 阻断感染的小鼠最初出现白细胞减少（CD4/CD8 T 细胞比值增加），随后出现白细胞增多（CD4/CD8 T 细胞比值降低）和显著的生化值升高。IFNAR 阻断感染的小鼠外周血单个核细胞（PBMCs）和组织中的凋亡细胞与病毒载量以及血液、脾脏和引流 LN 中的不同细胞因子水平相关，在 IFNAR 阻断感染的小鼠中，不同时间点的变化显著不同。
本研究首次对 I 型 IFN 阻断的免疫功能正常成年小鼠感染 BTV 血清型 1 进行了描述。这些发现将有助于研究发病机制和测试 BTV 疫苗的效果。
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