Variant enterovirus A71 found in immune-suppressed patient binds to heparan sulfate and exhibits neurotropism in B-cell-depleted mice
Kuo-Feng Weng,
Han Kang Tee,
Eirini D. Tseligka,
Valeria Cagno,
Gregory Mathez,
Stéphane Rosset,
Claude M. Nagamine,
Peter Sarnow,
Karla Kirkegaard,
Caroline Tapparel
Affiliations
Kuo-Feng Weng
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
Han Kang Tee
Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland
Eirini D. Tseligka
Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland
Valeria Cagno
Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland
Gregory Mathez
Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland
Stéphane Rosset
Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland
Claude M. Nagamine
Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
Peter Sarnow
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
Karla Kirkegaard
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Caroline Tapparel
Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland; Corresponding author
Summary: Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease outbreaks with neurological complications and deaths. We previously isolated an EV-A71 variant in the stool, cerebrospinal fluid, and blood of an immunocompromised patient who had a leucine-to-arginine substitution on the VP1 capsid protein, resulting in increased heparin sulfate binding. We show here that this mutation increases the virus’s pathogenicity in orally infected mice with depleted B cells, which mimics the patient’s immune status, and increases susceptibility to neutralizing antibodies. However, a double mutant with even greater heparin sulfate affinity is not pathogenic, suggesting that increased heparin sulfate affinity may trap virions in peripheral tissues and reduce neurovirulence. This research sheds light on the increased pathogenicity of variant with heparin sulfate (HS)-binding ability in individuals with decreased B cell immunity.
