Paired immunoglobulin-like receptor B is an entry receptor for mammalian orthoreovirus

Abstract

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.

NgR1 binding to reovirus reveals an unusual bivalent interaction and a new viral attachment protein

“…The extremely broad host range of reovirus in nature raises the possibility that NgR1 homologs from some species function as reovirus receptors and mediate reovirus disease, which is supported by a study suggesting that NgR1 is required for reovirus infection of neurons isolated from the Chinese tree shrew ( 87 ). In other species, additional receptors may function analogously to NgR1 and facilitate neuronal infection and consequent neuropathogenesis ( 88 ). A robust analysis of viral and host sequences required for reovirus–NgR1 interactions and functionality is warranted to understand how NgR1 influences both target cell selection and disease in animal models and humans.…”

Immune receptors and aging brain

“…Finally, LILRB2 and PIRB also function as binding and internalization receptors for reovirus serotype T3, which shows CNS neuronal tropism [ 119 ]. Given that viruses can directly bind to this and other immune receptors (e.g., TLRs [ 119 ]) and are a known risk factor for some neurodegenerative diseases [ 120 , 121 ], understanding in greater detail the interaction between external pathogens and internal DAMP-like molecule activation of receptors becomes a topic of interest.…”

“…Despite the overwhelming evidence linking viral infections to accelerated cognitive decline, the precise mechanisms through which viral pathogens create a conducive environment for neurodegeneration remain incompletely understood. TLRs, Ig-like receptors, and complement cascade components emerge as plausible candidates for mediating the augmented risk of neurodegeneration, given that various pathogenic epitopes act as ligands for these receptors in the brain, akin to their role in the immune system [ 9 , 119 ]. Importantly, pathogen binding in the brain might trigger neuroinflammatory, synaptotoxic, and neurotoxic responses similar to the binding of endogenous ligands, misfolded proteins, and DAMPs.…”