Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Nat Commun. 2023 May 5;14(1):2615. doi: 10.1038/s41467-023-38327-6.
Mammalian orthoreovirus (reovirus) infects most mammals and is associated with celiac disease in humans. In mice, reovirus infects the intestine and disseminates systemically to cause serotype-specific patterns of disease in the brain. To identify receptors conferring reovirus serotype-dependent neuropathogenesis, we conducted a genome-wide CRISPRa screen and identified paired immunoglobulin-like receptor B (PirB) as a receptor candidate. Ectopic expression of PirB allowed reovirus binding and infection. PirB extracelluar D3D4 region is required for reovirus attachment and infectivity. Reovirus binds to PirB with nM affinity as determined by single molecule force spectroscopy. Efficient reovirus endocytosis requires PirB signaling motifs. In inoculated mice, PirB is required for maximal replication in the brain and full neuropathogenicity of neurotropic serotype 3 (T3) reovirus. In primary cortical neurons, PirB expression contributes to T3 reovirus infectivity. Thus, PirB is an entry receptor for reovirus and contributes to T3 reovirus replication and pathogenesis in the murine brain.
哺乳动物正呼肠孤病毒（reovirus）感染大多数哺乳动物，并与人类的乳糜泻有关。在小鼠中，呼肠孤病毒感染肠道并全身传播，导致大脑中出现特定血清型的疾病模式。为了鉴定赋予呼肠孤病毒血清型依赖性神经发病机制的受体，我们进行了全基因组 CRISPRa 筛选，并将配对免疫球蛋白样受体 B（PirB）鉴定为受体候选物。PirB 的异位表达允许呼肠孤病毒结合和感染。呼肠孤病毒附着和感染需要 PirB 的细胞外 D3D4 区域。通过单分子力谱法测定，呼肠孤病毒与 PirB 的结合亲和力为 nM。有效的呼肠孤病毒内吞作用需要 PirB 信号基序。在接种的小鼠中，PirB 是脑内最大复制和神经嗜性血清型 3（T3）呼肠孤病毒完全神经致病性所必需的。在原代皮质神经元中，PirB 的表达有助于 T3 呼肠孤病毒的感染。因此，PirB 是呼肠孤病毒的进入受体，有助于 T3 呼肠孤病毒在小鼠大脑中的复制和发病机制。
