Emerging zoonotic viruses: new lessons on receptor and entry mechanisms

Abstract

Viruses enter the host cell by binding cellular receptors that allow appropriate delivery of the viral genome. Although the horizontal propagation of viruses feeds the continuous emergence of novel pathogenic viruses, the genetic variation of cellular receptors can represent a challenging barrier. The SARS coronavirus, henipaviruses and filoviruses are zoonotic RNA viruses that use bats as their reservoir. Their lethality for man has fostered extensive research both on the cellular receptors they use and their entry pathways. These studies have allowed new insights into the diversity of the molecular mechanisms underlying both virus entry and pathogenesis.

Figure 1

(a) Entry steps of SARS-CoV and pathogenic consequences, with (1) virus attachment to the cell via binding of S to ACE2, (2) activation of TMPRSS2 ectoprotease that leads to the cleavage and activation of virus S envelope protein into the fusion competent S1–S2 heterodimer, (3) fusion of the virus envelope with the plasma membrane to deliver the nucleocapsid into the cytoplasm and allow virus replication, (4) proteolytic cleavage by TMPRSS2 (and/or ADAM17/TACE) ectoprotease with shedding of the ectodomain of the majority of ACE2 molecules independently of their use by SARS-CoV leading to (5) lung failure. (b) Relationship between the affinity of SARS-CoV S protein with the ACE2 receptor, entry efficiency, pathogenicity and inter-human transmission.

Figure 2

Crystal structure of ephrinB2 in complex with EphA4, EphB2, EphB4, HeV and NiV G showing nearly identical binding modes and affinity ranking of ligands. Structures (PDB identification codes indicated in parenthesis) were drawn using FirstGlance in Jmol (http://molvis.sdsc.edu/fgij/). Phe120, Asn123, Trp125 and Leu129 of the F–G loop of ephrinB2 are decorated with golden circles for easier perception.

Figure 3

Model of filovirus entry. Virus binds to the cell surface via recognition of sugar moieties (blue branches) of GP1 by DC-SIGN or LECStin (light green) (1) to be immediately internalized by macropinocytosis (2) and migrate through the endocytic pathway (3) until the mucin-like domain (mucin) is cleaved off from GP1 by resident cathepsin B (cath B). This results in RBR (yellow star) being accessible for binding to the postulated receptor (dark green question mark) (4). An additional activation event (disulfide bridge reduction?) occurs (5). This triggers the conformational changes of GP2 (yellow) that mediates fusion of viral and endosomal membranes and ensures the delivery of the nucleocapsid (NC) into the cytosol (pale yellow background) where replication occurs (6). Because the postulated receptor (question mark) is predicted to be expressed at the cell surface, it has been included in every step of virus internalization. Although not yet documented, endosome structures 4 to 6 may successively represent early, maturing, late and possibly endolysosomes, because of the ∼1 h delay between the cell attachment and membrane fusion steps.