Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA.
Viruses and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA.
Nat Commun. 2024 Oct 30;15(1):9375. doi: 10.1038/s41467-024-53792-3.
Influenza virus pandemics are caused by viruses from animal reservoirs that adapt to efficiently infect and replicate in human hosts. Here, we investigate whether Interferon-Induced Transmembrane Protein 3 (IFITM3), a host antiviral factor with known human deficiencies, plays a role in interspecies virus infection and adaptation. We find that IFITM3-deficient mice and human cells can be infected with low doses of avian influenza viruses that fail to infect WT counterparts, identifying a new role for IFITM3 in controlling the minimum infectious virus dose threshold. Remarkably, influenza viruses passaged through Ifitm3 mice exhibit enhanced host adaptation, a result that is distinct from viruses passaged in mice deficient for interferon signaling, which exhibit attenuation. Our data demonstrate that IFITM3 deficiency uniquely facilitates potentially zoonotic influenza virus infections and subsequent adaptation, implicating IFITM3 deficiencies in the human population as a vulnerability for emergence of new pandemic viruses.
流感病毒大流行是由来自动物宿主的病毒引起的，这些病毒能够有效地适应并在人类宿主中复制。在这里，我们研究了干扰素诱导跨膜蛋白 3（IFITM3）——一种具有已知人类缺陷的宿主抗病毒因子——是否在种间病毒感染和适应中发挥作用。我们发现，IFITM3 缺陷型小鼠和人细胞可以被低剂量的禽流感病毒感染，而这些病毒无法感染 WT 对照，这为 IFITM3 在控制最小感染病毒剂量阈值方面确定了一个新的作用。值得注意的是，通过 Ifitm3 小鼠传代的流感病毒表现出增强的宿主适应性，这一结果与在缺乏干扰素信号的小鼠中传代的病毒不同，后者表现出衰减。我们的数据表明，IFITM3 缺陷独特地促进了潜在的人畜共患流感病毒感染及其随后的适应，这表明 IFITM3 缺陷在人类群体中是新出现大流行病毒的脆弱性因素。
