Reovirus, also known as mammalian orthoreovirus, infects most mammals. Two new projects from the Department of Pediatrics about this virus from Pengcheng Shang, PhD and Danica M. Sutherland, PhD expand further on how reovirus infects.
Shang’s project tilted “Paired immunoglobulin-like receptor B is an entry receptor for mammalian ortheoreovirus”, published in Nature Communications, talks about the infectivity of the virus within the brain because of the paired immunoglobulin-like receptor B (PirB). Reovirus is associated with celiac disease in humans, but in mice, it infects the intestine and disseminates systemically to cause serotype-specific patterns of disease in the brain. To identify receptors conferring reovirus serotype-dependent neuro- pathogenesis, Shang and his team conducted a genome-wide CRISPRa screen and identified PirB as a 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 mM 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.
Sutherland’s project titled “NgR1 binding to reovirus reveals an unusual bivalent interaction and a new viral attachment protein”, published in PNAS, talks about Nogo-66 receptor 1’s (NgR1) role in assisting reovirus and how the two bind. NgR1 binds a variety of structurally dissimilar ligands in the adult central nervous system to inhibit axon extension. Disruption of ligand binding to NgR1 and subsequent signaling can improve neuron outgrowth, making NgR1 an important therapeutic target for diverse neurological conditions such as spinal crush injuries and Alzheimer’s disease. Human NgR1 serves as a receptor for mammalian orthoreovirus (reovirus), but the mechanism of virus–receptor engagement is unknown. To elucidate how NgR1 mediates cell binding and entry of reovirus, Sutherland and their team defined the affinity of interaction between virus and receptor, determined the structure of the virus–receptor complex, and identified residues in the receptor required for virus binding and infection. Their studies revealed that central NgR1 surfaces form a bridge between two copies of viral capsid protein σ3, establishing that σ3 serves as a receptor ligand for reovirus. This unusual binding interface produces high-avidity interactions between virus and receptor to prime early entry steps. These studies refine models of reovirus cell-attachment and highlight the evolution of viruses to engage multiple receptors using distinct capsid components.
Congratulations to both Shang and Sutherland for their published articles! Follow the Department of Pediatrics on Twitter for more updates and articles from the department.