Single Amino Acid Substitutions Surrounding the Icosahedral Fivefold Symmetry Axis Are Critical for Alternative Receptor Usage of Foot-and-Mouth Disease Virus

Viruses. 2020 Oct 9;12(10):1147. doi: 10.3390/v12101147.


The integrins function as the primary receptor molecules for the pathogenic infection of foot-and-mouth disease virus (FMDV) in vivo, while the acquisition of a high affinity for heparan sulfate (HS) of some FMDV variants could be privileged to facilitate viral infection and expanded cell tropism in vitro. Here, we noted that a BHK-adapted Cathay topotype derivative (O/HN/CHA/93tc) but not its genetically engineered virus (rHN), was able to infect HS-positive CHO-K1 cells and mutant pgsD-677 cells. There were one or three residue changes in the capsid proteins of O/HN/CHA/93tc and rHN, as compared with that of their tissue-originated isolate (O/HN/CHA/93wt). The phenotypic properties of a set of site-directed mutants of rHN revealed that E83K of VP1 surrounding the fivefold symmetry axis was necessary for the integrin-independent infection of O/HN/CHA/93tc. L80 in VP2 was essential for the occurrence of E83K in VP1 during the adaptation of O/HN/CHA/93wt to BHK-21 cells. L80M in VP2 and D138G in VP1 of rHN was deleterious, which could be compensated by K83R of VP1 for restoring an efficient infection of integrin-negative CHO cell lines. These might have important implications for understanding the molecular and evolutionary mechanisms of the recognition and binding of FMDV with alternative cellular receptors.

Keywords: alternative cellular receptors; foot-and-mouth disease virus; integrin-independent endocytic pathway; phenotypic properties; site-directed mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Binding Sites / physiology*
  • CHO Cells
  • Capsid Proteins / genetics*
  • Capsid Proteins / metabolism*
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Foot-and-Mouth Disease / virology
  • Foot-and-Mouth Disease Virus / genetics
  • Foot-and-Mouth Disease Virus / metabolism*
  • Genome, Viral / genetics
  • Heparitin Sulfate / metabolism
  • Mice
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • Virus Attachment*
  • Virus Internalization


  • Capsid Proteins
  • Receptors, Virus
  • VP1 protein, Foot-and-mouth disease virus
  • Heparitin Sulfate