NRP1 is a receptor for mammalian orthoreovirus engaged by distinct capsid subunits

Area of Science:

• Virology
• Immunology
• Neuroscience

Background:

• Mammalian orthoreovirus (reovirus) is a nonenveloped virus causing intestinal infections and spreading to secondary sites, including the central nervous system (CNS).
• The precise mechanisms of reovirus systemic dissemination and neuronal targeting are not fully understood.
• Viral entry often involves multiple host cell engagement factors.

Purpose of the Study:

• To identify the specific host cell receptor utilized by reovirus for entry and systemic spread.
• To elucidate the molecular mechanisms underlying reovirus-neuropilin 1 (NRP1) interaction.
• To determine the role of NRP1 in reovirus pathogenesis, particularly neurovirulence.

Main Methods:

• Identification of murine neuropilin 1 (mNRP1) as a reovirus binding protein.
• Characterization of the virus-receptor binding affinity and interaction interface.
• Genetic manipulation of reovirus capsid proteins (σ3 and λ2) to assess binding and infectivity.
• In vivo studies using capsid mutants to evaluate reovirus dissemination and neurovirulence in mice.

Main Results:

• Murine neuropilin 1 (mNRP1) was identified as a high-affinity receptor for reovirus.
• Reovirus-NRP1 interaction involves multivalent binding between viral capsid proteins (σ3 and λ2) and extracellular domains of NRP1.
• Capsid mutants unable to bind NRP1 showed reduced systemic dissemination and neurovirulence in a mouse model.
• NRP1 plays a significant role in facilitating reovirus entry and contributing to its pathogenesis.

Conclusions:

• Neuropilin 1 (NRP1) serves as a critical entry receptor for mammalian orthoreovirus.
• The multivalent interaction between reovirus capsid proteins and NRP1 is essential for viral dissemination and neurovirulence.
• Understanding NRP1's role provides insights into viral pathogenesis and potential therapeutic strategies.