Abstract
Enteroviruses are among the most common human infectious agents. While infections are often mild, the severe neuropathogenesis associated with recent outbreaks of emerging non-polio enteroviruses, such as EV-A71 and EV-D68, highlights their continuing threat to public health. In recent years, our understanding of how non-polio enteroviruses co-opt cellular pathways has greatly increased, revealing intricate host–virus relationships. In this review, we focus on newly identified mechanisms by which enteroviruses hijack the cellular machinery to promote their replication and spread, and address their potential for the development of host-directed therapeutics. Specifically, we discuss newly identified cellular receptors and their contribution to neurotropism and spread, host factors required for viral entry and replication, and recent insights into lipid acquisition and replication organelle biogenesis. The comprehensive knowledge of common cellular pathways required by enteroviruses could expose vulnerabilities amenable for host-directed therapeutics against a broad spectrum of enteroviruses. Since this will likely include newly arising strains, it will better prepare us for future epidemics. Moreover, identifying host proteins specific to neurovirulent strains may allow us to better understand factors contributing to the neurotropism of these viruses.
Highlights
Poliovirus (PV), which once caused severe neuropathogenesis, is on the verge of eradication following widespread vaccination
Understanding how this broad class of viruses depends on common cellular pathways uncovers basic aspects of cellular biology, reveals intricate host virus relationships, and leads to possible targets for host-directed antiviral therapy that will be critical to combat the rising threat non-polio enteroviruses (NPEVs) pose to human health
SETD3 was critically important for in vivo pathogenesis, as it was shown that Setd3-/- neonatal mice were completely protected from lethal challenge with EV-A71 and CV-A10 upon intracranial injection. These findings demonstrate that SETD3 controls pathogenesis for a large class of enteroviruses with a strong impact on human health
Summary
Poliovirus (PV), which once caused severe neuropathogenesis, is on the verge of eradication following widespread vaccination. While resistance to drugs targeting viral factors can rapidly emerge due to the fast mutation rate of the viral genome, resistance to hosttargeting drugs would require the virus to utilize an alternative host factor or become less dependent on the host factor for their infection This is possible, these resistance mutations would likely not overlap with those that occur with direct antiviral therapeutics. Understanding how this broad class of viruses depends on common cellular pathways uncovers basic aspects of cellular biology, reveals intricate host virus relationships, and leads to possible targets for host-directed antiviral therapy that will be critical to combat the rising threat NPEVs pose to human health
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