Molecular mechanism of antibody neutralization of coxsackievirus A16

Zhang, Chao; Liu, Caixuan; Shi, Jinping; Wang, Yalei; Xu, Cong; Ye, Xiaohua; Liu, Qingwei; Li, Xue; Qiao, Weihua; Yin, Yannan; Cong, Yao; Huang, Zhong

doi:10.1038/s41467-022-35575-w

Cited by 3 publications

(4 citation statements)

References 67 publications

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“…Polyclonal antibodies were raised against CVA10 by multiple immunization of BALB/c mice with purified CVA10/Kowalik formulated with alum. MAb 2A11 is a mouse IgA antibody with strong neutralizing activity against CVA10, which was prepared in our lab according to previously described protocols [ 36 , 37 ].…”

Section: Methodsmentioning

confidence: 99%

“…Escape mutants were selected according to a previously described protocol [ 37 ]. Briefly, 100 TCID 50 of CVA10/Kowalik was incubated with serially diluted hKRM1-Fc protein for 1 h at 37°C and then added to RD cells grown in 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…Viral particles were purified according to a previously described protocol [ 37 ]. Briefly, RD cells grown in 15-cm dishes were infected with CVA10-WT or CVA10-N142A at a MOI of 0.01.…”

Section: Methodsmentioning

confidence: 99%

“…antibody with strong neutralizing activity against CVA10, which was prepared in our lab according to previously described protocols [36,37].…”

Section: Plos Pathogensmentioning

confidence: 99%

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VP2 residue N142 of coxsackievirus A10 is critical for the interaction with KREMEN1 receptor and neutralizing antibodies and the pathogenicity in mice

Li,

Liu,

Yan

et al. 2023

PLoS Pathog

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Coxsackievirus A10 (CVA10) has recently emerged as one of the major causative agents of hand, foot, and mouth disease. CVA10 may also cause a variety of complications. No approved vaccine or drug is currently available for CVA10. The residues of CVA10 critical for viral attachment, infectivity and in vivo pathogenicity have not been identified by experiment. Here, we report the identification of CVA10 residues important for binding to cellular receptor KREMEN1. We identified VP2 N142 as a key receptor-binding residue by screening of CVA10 mutants resistant to neutralization by soluble KREMEN1 protein. The receptor-binding residue N142 is exposed on the canyon rim but highly conserved in all naturally occurring CVA10 strains, which provides a counterexample to the canyon hypothesis. Residue N142 when mutated drastically reduced receptor-binding activity, resulting in decreased viral attachment and infection in cell culture. More importantly, residue N142 when mutated reduced viral replication in limb muscle and spinal cord of infected mice, leading to lower mortality and less severe clinical symptoms. Additionally, residue N142 when mutated could decrease viral binding affinity to anti-CVA10 polyclonal antibodies and a neutralizing monoclonal antibody and render CVA10 resistant to neutralization by the anti-CVA10 antibodies. Overall, our study highlights the essential role of VP2 residue N142 of CVA10 in the interactions with KREMEN1 receptor and neutralizing antibodies and viral virulence in mice, facilitating the understanding of the molecular mechanisms of CVA10 infection and immunity. Our study also provides important information for rational development of antibody-based treatment and vaccines against CVA10 infection.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Viral particles were purified according to a previously described protocol [ 37 ]. Briefly, RD cells grown in 15-cm dishes were infected with CVA10-WT or CVA10-N142A at a MOI of 0.01.…”

Section: Methodsmentioning

confidence: 99%

“…antibody with strong neutralizing activity against CVA10, which was prepared in our lab according to previously described protocols [36,37].…”

Section: Plos Pathogensmentioning

confidence: 99%

See 2 more Smart Citations

VP2 residue N142 of coxsackievirus A10 is critical for the interaction with KREMEN1 receptor and neutralizing antibodies and the pathogenicity in mice

Li,

Liu,

Yan

et al. 2023

PLoS Pathog

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Broadly therapeutic antibody provides cross-serotype protection against enteroviruses via Fc effector functions and by mimicking SCARB2

Zhu,

Wu,

Huang

et al. 2024

Nat Microbiol

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Identification of four neutralizing antigenic sites on the enterovirus D68 capsid

Dai,

Li,

Liu

et al. 2023

J Virol

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Enterovirus D68 (EV-D68) is an emerging human pathogen associated with respiratory diseases and/or acute flaccid myelitis. Neutralizing antigenic sites of EV-D68 have not yet been comprehensively studied. In this study, we generated multiple neutralizing monoclonal antibodies (MAbs) directed against EV-D68 prototype or clinical strains. All these antibodies can inhibit EV-D68 attachment. The antibody epitopes were identified by selection and sequence analysis of prototype or clinical strain-derived neutralization-resistant mutants. The epitopes were then grouped into four distinct neutralizing antigenic sites (I to IV) by cross-neutralization analysis of the mutants with the MAbs and by spatial considerations. Site I, including residues 81, 85, and 87 of VP1 protein, is located in the VP1 BC loop, near the fivefold axis, and at the north rim of the canyon (the receptor binding site). Site II, involving residues 137, 139, and 142 of VP2, is situated in the VP2 EF loop and at the south rim of the canyon. Site III is composed of VP1 C-terminal residues 285 and 293 and resides on the south side of the canyon of neighboring asymmetric unit. Site IV contains residue 70 (βB strand) of VP2 from an asymmetric unit and residues 74 and 79 (BC loop) of VP3 from an adjacent unit and is located around the threefold axis. The four antigenic sites show various degrees of sequence variation. The identification of the four neutralizing antigenic sites on EV-D68 capsid provides a better understanding of the recognition of EV-D68 by neutralizing antibodies and viral evolution and immune escape. IMPORTANCE Enterovirus D68 (EV-D68) is an emerging respiratory pathogen associated with acute flaccid myelitis. Currently, no approved vaccines or antiviral drugs are available. Here, we report four functionally independent neutralizing antigenic sites (I to IV) by analyses of neutralizing monoclonal antibody (MAb)-resistant mutants. Site I is located in the VP1 BC loop near the fivefold axis. Site II resides in the VP2 EF loop, and site III is situated in VP1 C-terminus; both sites are located at the south rim of the canyon. Site IV is composed of residue in VP2 βB strand and residues in the VP3 BC loop and resides around the threefold axis. The developed MAbs targeting the antigenic sites can inhibit viral binding to cells. These findings advance the understanding of the recognition of EV-D68 by neutralizing antibodies and viral evolution and immune escape and also have important implications for the development of novel EV-D68 vaccines.

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Molecular mechanism of antibody neutralization of coxsackievirus A16

Cited by 3 publications

References 67 publications

VP2 residue N142 of coxsackievirus A10 is critical for the interaction with KREMEN1 receptor and neutralizing antibodies and the pathogenicity in mice

VP2 residue N142 of coxsackievirus A10 is critical for the interaction with KREMEN1 receptor and neutralizing antibodies and the pathogenicity in mice

Broadly therapeutic antibody provides cross-serotype protection against enteroviruses via Fc effector functions and by mimicking SCARB2

Identification of four neutralizing antigenic sites on the enterovirus D68 capsid

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