口蹄疫病毒O型东南亚拓扑型抗原变异研究

doi:10.3864/j.issn.0578-1752.2024.15.014

Abstract

Abstract:

【Objective】The continuous variation of foot-and-mouth disease virus (FMDV) serotype O easily leads to the decrease of antigen matching between the currently used vaccine and the circulating strain, resulting in poor immune effect and sporadic outbreaks. In recent years, Southeast Asia (SEA) topotype epidemic of FMDV serotype O has been active and constantly changing, which has continued to exert pressure on foot-and-mouth disease prevention. Systematic analysis of specific antigen sites of serotype O FMDV strains and sequence differences of different topological strains and identification of key amino acids of antigen variation could provide basis for FMD antigen molecular design, and provide guidance for FMD prevention and control. 【Method】In this study, 10 bovine-derived monoclonal neutralizing antibodies specific for SEA topotype strains were used to screen escape mutants by antibody pressure in strain O/GSLX/2010 (O/Mya/98 lineage) to identify the key amino acids. The viral cross-neutralization tests were performed using bovine polyclonal antiserum samples (32 samples) and escape mutants to analyze the immunodominant epitopes of SEA topotype strains. The differences in this epitope between different topotype strains were analyzed by sequence alignment. Reverse genetic technique was used to introduce differential epitopes into FMDV serotype O classic vaccine strain O/HN/CHA/93 (Cathay topotype), and the rescued point mutant strains were sequenced and identified by indirect immunofluorescence assay. Virus plaque detection and one-step growth curve were used to detect the replication dynamics of the virus. Using SEA topotype strain specific monoclonal neutralization antibodies, the antigenicity of the rescue mutant was analyzed by neutralization test, the key amino acids affecting the antigenicity of the virus were identified, and the influence of the amino acids changes at the specific site of the strain on the antigen profile was evaluated. 【Result】SEA topotype-specific epitopes were mainly concentrated in the B-C and C-D loop of VP1, which belonged to antigenic site 3. Most of the 10 mAbs (8/10) recognized epitopes on VP1, among which 6 mAbs (A19, B55, B74, C5, F53, and F166) recognized key amino acids located in the B-C loop (T43, K45) and C-D loop (P58) of VP1, and the other 2 mAbs (B66 and F41) identified key amino acids at the C-terminus of VP1. The results of virus cross-neutralization test showed that the changes of amino acids 43 of VP1 and 131 of VP3 significantly reduced the antibody titer of bovine polyclonal antisera. The sequence analysis of different lineages of FMDV serotype O (26 strains) revealed that amino acids 28, 47, 56, and 58 in the B-C/C-D loop of VP1 were different in the three topotype. Using reverse genetic technology, the virus-specific epitope was successfully introduced into Cathay topotype (O/HN/CHA/93) and saved 6 FMDV point mutants: POZ-GSLX-M58, POZ-GSLX-M56/58, POZ-GSLX-M28/58, POZ-GSLX-M47/58, POZ-GSLX-M28/58/47, and POZ-GSLX-M47/56/58. The results of microneutralization test showed that 56/58 VP1 played a key role in the antigenicity of the virus. However, further additions of mutations at positions 28 and 47 reduced the neutralization of antibody B83, affecting the antigenicity of the strain itself. Therefore, the changes in amino acids at positions 56 and 58 on VP1 could extend the effectiveness and breadth of SEA topotype specific neutralization of mAbs against O/HN/CHA/93 strains.【Conclusion】Amino acids 56 and 58 on the structural protein VP1 of FMDV serotype O were key sites causing antigenic variation in SEA topotype, and introducing these antigenic determinants could expand the neutralization potency and breadth of SEA topotype-specific neutralizing mAbs, and effectively expand the antigenic profile of FMDV O/HN/CHA/93. This study provided an important reference for FMD prevention and vaccine design.

Key words: foot-and-mouth disease virus, strain specific neutralizing antibody, antigenic variation

WANG Li, LI Kun, HUANG ShuLun, LI FengJuan, WANG Sheng, LU ZengJun, LIU ZaiXin. Antigenic Variation of Foot-and-Mouth Disease Virus Serotype O in Southeast Asia Topotype[J].Scientia Agricultura Sinica, 2024, 57(15): 3093-3104.

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References 33

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单克隆抗体 mAbs	中和抗体效价 Neutralization antibody titer
单克隆抗体 mAbs	O/GSLX/2010	O/CHA/Mya33	O/GZSB	O/Mya/98	O/HNNY/2022
A19	>50.00	>50.00	48.69	4.56	35.41
B55	49.92	>50.00	24.04	2.54	>50.00
B66	37.50	>50.00	>50.00	1.76	>50.00
B74	3.91	2.93	2.81	1.17	>50.00
B83	16.64	27.56	46.42	6.89	>50.00
C5	>50.00	>50.00	>50.00	17.40	>50.00
F41	3.96	6.33	2.64	1.32	>50.00
F53	17.63	13.12	35.25	3.30	47.00
F136	31.57	31.57	15.42	2.59	14.73
F166	4.29	2.87	2.87	0.72	11.47

单克隆抗体 mAbs	亲本毒 Parent virus	突变位置 Residue change	突变频率 Frequency of mutants	中和浓度 Neutralization concentration (μg·mL^-1)
B74	O/GSLX/2010	VP1 T43P	1/8	>600
		VP1 P58S	3/8	>600
		VP1 T43A, P58S	4/8	>600
F166	O/GSLX/2010	VP1 P58S	3/5	>600
F166	O/GSLX/2010	VP1 K45N, P58S	2/5	>600
B55	O/GSLX/2010	VP1 P58S	5/6	>600
B55	O/GSLX/2010	VP1 P58H	1/6	>600
A19	O/GSLX/2010	VP1 P58S	4/4	>600
C5	O/GSLX/2010	VP1 P58S	3/4	>600
C5	O/GSLX/2010	VP1 V209A	1/4	>600
F53	O/GSLX/2010	VP1 K45Q	2/5	>600
F53	O/GSLX/2010	VP1 D99G	3/5	>600
F41	O/GSLX/2010	VP1 A199D	5/8	>600
		VP1 A199D; VP3 E131D	1/8	>600
		VP2 P74S; VP3 E131D	1/8	>600
		VP1 A199D; VP3 E131D	1/8	>600
B66	O/GSLX/2010	VP1 V209A	2/5	>600
		VP1 A207S	1/5	>600
		VP1 Q211R	1/5	>600
		VP1 Q211R; VP2 V199E, N202K; VP3 G196V	1/5	>600
B83	O/GSLX/2010	VP2 P195T	2/6	>600
B83	O/GSLX/2010	VP2 P195S	4/6	>600
F136	O/GSLX/2010	VP3 E131D	6/7	>600
F136	O/GSLX/2010	VP1 A199D; VP3 E131D	1/7	>600

Antigenic Variation of Foot-and-Mouth Disease Virus Serotype O in Southeast Asia Topotype

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