Department of Medicine, Division of Immunology, Uniformed Services University of the Health Sciences , Bethesda, MD, USA.
Department of Pathology, Uniformed Services University of the Health Sciences , Bethesda, MD, USA.
Hum Vaccin Immunother. 2020 Sep 1;16(9):2222-2237. doi: 10.1080/21645515.2020.1713605. Epub 2020 Mar 4.
We have engineered a Human Immune System (HIS)-reconstituted mouse strain (DRAGA mouse: HLA-A2. HLA-DR4. Rag1 KO. IL-2Rγc KO. NOD) in which the murine immune system has been replaced by a long-term, functional HIS via infusion of CD34 hematopoietic stem cells (HSC) from cord blood. Herein, we report that the DRAGA mice can sustain inducible and transmissible H1N1 and H3N2 influenza A viral (IAV) infections. DRAGA female mice were significantly more resilient than the males to the H3N2/Aichi infection, but not to H3N2/Hong Kong, H3N2/Victoria, or H1N1/PR8 sub-lethal infections. Consistently associated with large pulmonary hemorrhagic areas, both human and murine mRNA transcripts were undetectable in the damaged lung tissues but not in livers of DRAGA mice advancing to severe H1N1/PR8 infection. Infected DRAGA mice mounted a neutralizing anti-viral antibody response and developed lung-resident CD103 T cells. These results indicate that the DRAGA mouse model for IAV infections can more closely approximate the human lung pathology and anti-viral immune responses compared to non-HIS mice. This mouse model may also allow further investigations into gender-based resilience to IAV infections, and may potentially be used to evaluate the efficacy of IAV vaccine regimens for humans.
我们构建了一种人免疫系统（HIS）重建的小鼠品系（DRAGA 小鼠：HLA-A2、HLA-DR4、Rag1 KO、IL-2Rγc KO、NOD），其中通过输注来自脐血的 CD34 造血干细胞（HSC），替代了长期功能性 HIS。在此，我们报告称，DRAGA 小鼠可以维持诱导和可传播的 H1N1 和 H3N2 甲型流感病毒（IAV）感染。与雄性相比，DRAGA 雌性对 H3N2/Aichi 感染的抵抗力更强，但对 H3N2/Hong Kong、H3N2/Victoria 或 H1N1/PR8 亚致死感染的抵抗力没有更强。与肺部大量出血区域一致，在进展为严重 H1N1/PR8 感染的 DRAGA 小鼠的受损肺组织中，人源和鼠源 mRNA 转录物均无法检测到，但在肝脏中可以检测到。感染的 DRAGA 小鼠产生了中和抗病毒抗体反应，并产生了肺驻留的 CD103 T 细胞。这些结果表明，与非 HIS 小鼠相比，DRAGA 小鼠 IAV 感染模型更能近似人类肺部病理学和抗病毒免疫反应。该小鼠模型还可能进一步研究 IAV 感染的性别抗性，并可能被用于评估人类 IAV 疫苗方案的疗效。
