Variant enterovirus A71 found in immune-suppressed patient binds to heparan sulfate and exhibits neurotropism in B-cell-depleted mice

SUMMARY

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease outbreaks with neurological complications and deaths. The team led by Prof Caroline Tapparel at UNIGE, previously isolated an EV-A71 variant which emerged  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. Here, in collaboration with Prof. Karla Kirkegaard at the Standford University School of Medicine, they show that this mutation increases the virus’s pathogenicity in orally infected mice with depleted B cells, which mimics the patient’s immune status. The mutation also increases susceptibility to neutralizing antibodies, making it unlikely to emerge in an immune-competent host. 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.

This study was funded by Swiss National Foundation, Faculty of Medicine from the University of Geneva, NIH and Stanford University School of Medicine.

Full article:  DOI 10.1016/j.celrep.2023.112389

Why is this important?

Classified in the genus Enterovirus, within the family Picornaviridae, enterovirus A71 (EV-A71) is the most virulent EV after poliovirus, causing major outbreaks of hand, foot and mouth disease that can be accompanied by severe neurological complications and death. No antiviral compound is currently available to treat these infections.

In 2012, Prof Carolin Tapparel identified a mutation in the VP1 capsid protein of EV-A71, a substitution of leucine (L) for a positively charged arginine (R) at position 97 of VP1 (L97R), which was acquired during disseminated infection in a patient with B-cell depletion treated with rituximab for chronic lymphocytic leukaemia. In this study, the authors mimicked the same situation in a mouse model to study the pathogenesis of this virus in immunocompromised patients.

Their results showed that this pathogenic mutation, VP1 L97R, confers increased heparin sulfate binding capacity, a greater likelihood of invading the host brain, and increased overall viral virulence in a mouse model of oral infection. While this mutation is likely to make the virus vulnerable to elimination by B lymphocytes due to increased susceptibility to host neutralising antibodies, it does highlight the possibility that the VP1-97R virus may find a facilitated route of infection to invade critical tissues, leading to severe disease. Based on this study and the original case published before, special attention should be paid to the choice of immunosuppressive therapies administered to patients. Rituximab or other B-cell depleting chemotherapies seem to favour the emergence of EV-A71 variants with an increased ability to bind to cellular receptors and with a higher neurotropic potential.

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