ArticleJournal of virology2026
A single residue in the VP3 capsid protein governs virulence and informs live-attenuated vaccine design for coxsackievirus A6.
Article in Journal of virology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Coxsackievirus A6 (CVA6) is a major pathogen of hand, foot, and mouth disease, yet the viral determinants of its severe pathogenicity remain undefined, hampering intervention strategies. Here, by comparing a highly lethal clinical isolate (CVA6-HeB) with an attenuated strain (CVA6-TW141), we identified the capsid-encoding P1 region as the primary virulence determinant in neonatal mice. Fine-mapping identified a single critical residue at position 238 of VP3 (VP3-238): glutamic acid (E) in virulent CVA6-HeB versus alanine (A) in attenuated CVA6-TW141. Introducing E238 into the attenuated CVA6-TW141 was sufficient to confer lethality, and conversely, reverting it to alanine in the lethal CVA6-HeB completely abolished virulence, demonstrating that VP3-E238 is necessary and sufficient for lethal disease. E238 is dominant (>93%) in circulating CVA6 strains, suggesting a significant fitness advantage. This residue is situated at the edge of the canyon, a key receptor-binding site. Replacing E238 with alanine (E238A) did not affect virion assembly or growth in cultured cells. However, this mutation drastically reduced binding to the essential murine entry receptor KREMEN1 and attenuated virulence by over 10,000-fold in mice, correlating with significantly lower tissue viral loads and pathology. Based on this mechanism, we rationally designed a live-attenuated vaccine candidate by introducing the attenuating E238A mutation. Immunization with this candidate provided complete protection against a subsequent lethal challenge with a heterologous CVA6 strain. Our study defines VP3-E238 as a key molecular switch for CVA6 pathogenicity and establishes a foundation for rational vaccine development. IMPORTANCE: Hand, foot, and mouth disease is a common childhood illness increasingly caused by coxsackievirus A6 (CVA6), which can sometimes lead to severe complications. Currently, there are no specific vaccines or treatments available against CVA6. We identified the precise reason for the differing virulence between CVA6 strains. Comparing a lethal strain with a harmless one revealed a single determinant: residue 238 on the VP3 capsid protein. A glutamic acid ("E") at this site confers virulence, while alanine ("A") results in attenuation. By engineering an "E" to "A" mutation, we created a virus that is safe in mice but remains immunogenic. This engineered strain, used as a live vaccine, provided complete protection against lethal CVA6 challenge. Our work pinpoints a key virulence switch and presents a direct strategy for developing a safe CVA6 vaccine.
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