Return of the Neurotropic Enteroviruses: Co-Opting Cellular Pathways for Infection

Figures

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  Figure 1. Main receptors for human enteroviruses. Enteroviruses A–D contain neurotropic viruses that are associated with encephalitis, meningitis, and acute flaccid paralysis. Rhinoviruses A–C contain respiratory viruses that are the causative agents of the common cold. Representative EV serotypes are named here.

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  Figure 2. Speculative model of EV-A71 spread from the primary site of replication in the intestine to the CNS. There are three proposed phases of EV-A71 systemic infection: (1) initial replication in the gut, (2) dissemination to the blood compartment or immune cells, and (3) subsequent invasion of the CNS by infecting extraneural tissues to access motor neurons or by directly crossing the BBB. EV-A71 utilizes many receptors to promote its infection of various tissues. SCARB2 and PSGL-1 are the primary receptors. SCARB2 is broadly required for dissemination to many tissues, while PSGL-1 is found primarily on leukocytes and is important for the viremia phase of infection. Additional receptors including Vimentin and Prohibitin have been implicated in EV-A71 infection of the CNS, while the microbiome plays a role in initial infection of the gut leading to widespread EV-A71 infection.

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  Figure 3. Cellular factors required for viral replication. (1) Genome replication takes place on virus induced membranous replication organelles (ROs). To establish the massive web of replication organelles during infection, EVs upregulate phospholipid biosynthesis. Upon infection, the import of free fatty acids (FFAs) and their storage in lipid droplets (LDs) is increased. FFAs serve as substrates for phospholipid biosynthesis. EVs scavenge FFAs from lipid droplets to sustain the production of new lipids that drive RO biogenesis. (2) EV viral proteins recruit host proteins to generate a favorable lipid environment on developing ROs for viral replication. Viral proteins recruit PI4KB to enrich replication organelle membranes with the phospholipid PI4P. OSBP is redirected to ROs to transport cholesterol from the ER by shuttling PI4P down its concentration gradient. At the ER membrane, Sac1 hydrolyzes PI4P to phosphatidylinositol (PI), which is transferred back to the ROs by PITPb. (3) The viral RNA polymerase 3Dpol replicates the viral genome in coordination with several host and viral proteins. The viral genome is bound by the viral protein VPg (3B), which is required as a primer for…