Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine (TiHo), 30559 Hannover, Germany.
Viruses. 2023 Mar 23;15(4):814. doi: 10.3390/v15040814.
Dengue virus serotypes 1 to 4 (DENV1-4) place nearly half the global population at risk of infection and the licenced tetravalent dengue vaccine fails to protect individuals who have not previously been exposed to DENV. The development of intervention strategies had long been hampered by the lack of a suitable small animal model. DENV does not replicate in wild-type mice due to its inability to antagonise the mouse type I interferon (IFN) response. Mice deficient in type I IFN signalling ( mice) are highly susceptible to DENV infection, but their immunocompromised status makes it difficult to interpret immune responses elicited by experimental vaccines. To develop an alternative mouse model for vaccine testing, we treated adult wild-type mice with MAR1-5A3-an IFNAR1-blocking, non-cell-depleting antibody-prior to infection with the DENV2 strain D2Y98P. This approach would allow for vaccination of immunocompetent mice and subsequent inhibition of type I IFN signalling prior to challenge infection. While mice quickly succumbed to infection, MAR1-5A3-treated mice did not show any signs of illness but eventually seroconverted. Infectious virus was recovered from the sera and visceral organs of mice, but not from those of mice treated with MAR1-5A3. However, high levels of viral RNA were detected in the samples of MAR1-5A3-treated mice, indicating productive viral replication and dissemination. This transiently immunocompromised mouse model of DENV2 infection will aid the pre-clinical assessment of next-generation vaccines as well as novel antiviral treatments.
登革病毒血清型 1 至 4（DENV1-4）使近一半的全球人口面临感染风险，而许可的四价登革热疫苗不能保护以前未接触过 DENV 的个体。由于缺乏合适的小动物模型，干预策略的发展长期受到阻碍。由于无法拮抗小鼠 I 型干扰素（IFN）反应，DENV 无法在野生型小鼠中复制。缺乏 I 型 IFN 信号（ IFNAR1-/- ）的小鼠对 DENV 感染高度敏感，但它们免疫功能低下的状态使得难以解释实验疫苗引起的免疫反应。为了开发用于疫苗测试的替代小鼠模型，我们在用 DENV2 株 D2Y98P 感染之前，用 MAR1-5A3（一种 IFNAR1 阻断、非细胞耗竭抗体）处理成年野生型小鼠。这种方法可以对免疫功能正常的小鼠进行疫苗接种，并在挑战感染前抑制 I 型 IFN 信号。虽然 IFNAR1-/- 小鼠很快死于感染，但 MAR1-5A3 处理的小鼠没有任何疾病迹象，但最终血清转化。从 IFNAR1-/- 小鼠的血清和内脏器官中回收了传染性病毒，但从 MAR1-5A3 处理的小鼠中未回收。然而，在 MAR1-5A3 处理的小鼠样本中检测到高水平的病毒 RNA，表明病毒复制和传播活跃。这种 DENV2 感染的短暂免疫功能低下的小鼠模型将有助于下一代疫苗和新型抗病毒治疗的临床前评估。
