诱导型表达H5N1亚型禽流感病毒HA蛋白的乳酸乳球菌的构建及其对鸭的免疫原性分析

doi:10.11843/j.issn.0366-6964.2025.02.027

Abstract

Abstract:

Avian influenza, caused by avian influenza viruses, is a highly contagious disease characterized by high mortality rates among infected poultry, posing significant health risks to poultry and economic burdens. However, the majority of duck farming comprises small-scale and free-range practices, where environmental conditions vary and ducks are prone to diseases. In such scenarios, traditional vaccination practices present challenges such as inconvenient injection and immunological stress. To tackle this issue, this study devised a method to produce a convenient and safe oral biological agent of hemagglutinin (HA) tailored specifically for ducklings. We constructed the anchoring sequence (pgsA, BmpA, cA, and M6)-GFP reporter expression system, enabling the visualization of different anchoring sequences' effects on surface-displayed proteins in Lactococcus lactis (L. lactis). With this system, we successfully identified BmpA and cA as efficient anchoring sequences in L. lactis. After comparing the expression efficiency of HA in L. lactis and optimizing the codons, we selected the optimized HA gene sequence and connected it with BmpA and cA. Then, we co-integrated them into the expression plasmids of L. lactis. Subsequently, we introduced the constructed expression plasmids into L. lactis containing the integrated HA1 gene in the genome, thereby generating recombinant L. lactis capable of both inducible secretory expression and surface display of HA(NZB-HA1-pNZ8148-BmpA-HA1 and NZB-HA1-pNZ8148-HA1-cA). The ELISA results indicated that orally administered inducible secretory-surface display recombinant L. lactis eliciteds superior levels of HA-specific IgG in duckling serum compared to single-expression recombinant L. lactis treatment. This study successfully established the Anchoring sequence-GFP screening system for Lactobacillus, identifying efficient anchoring sequences suitable for L. lactis, thereby achieving efficient expression of HA on the surface of L. lactis. Subsequently, in conjunction with the genomic secretion expression, we successfully obtained an oral biological agent with satisfactory HA immunogenicity for ducklings. This achievement offers a practical and feasible strategy for the subsequent development of convenient and safe avian influenza oral vaccines.

Key words: anchoring sequence, Lactococcus lactis, avian influenza, duckling, HA

CLC Number:

S834
Q939.94

WU Jiahui, SHEN Shiyan, DENG Jinbo, WU Haiyang, REN Zhixin, WU Yangbo, HUANG Juan, HUANG Haobin, PAN Weixiong, ZHAO Zengjue, HE Rongxiao, SUN Chongjun, ZHANG Linghua. Construction of Recombinant Lactococcus lactis Inducible Expressing HA Protein of H5N1 Subtype Avian Influenza Virus and Analysis of Its Immunogenicity in Ducks[J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(2): 774-787.

Figures/Tables 11

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名称 Names	特征 Characteristics	来源 Reference or source
质粒Plasmids
pNZ8148	乳酸菌表达质粒	本实验室保存
pUC-pgsA	锚定序列	本实验室保存
pUC-BmpA	锚定序列	本实验室保存
pUC-GW-cA-M6	锚定序列	本实验室保存
pUC19-GFP		本实验室保存
pUC57-HA0	带有信号肽序列SPUsp45	苏州金唯智生物科技有限公司合成
pUC57-HA1	HA乳酸菌偏好性密码子优化	苏州金唯智生物科技有限公司合成
pJW4.1n	乳酸菌基因组敲入质粒	陆军军医大学王竞老师惠赠^[15]
菌株Strains
大肠杆菌DH5α		本实验室保存
大肠杆菌MC1061		本实验室保存
乳酸乳球菌NZB	LacZ基因整合到基因组	陆军军医大学王竞老师惠赠^[15]

名称	引物序列(5′→3′)
Name	Primer sequences
SP F	ATGAAAAAAAAGATTATCTCAGCTATTTT
SP R	CAATGCAAATTTGATCAGCGTAAACACCTGA
HA0 F	ATAAGGAGGCACTCAAAATGAAAAAAAAGATTATCTC
HA0 R	CATATTAAATATTCTCCTCTTAAATGCAAATTCTGCATT
HA1 F	TCAGGTGTTTACGCTGATCAAATTTGCATTGGCTA
HA1 R	CATATTAAATATTCTCCTCTAAATACAAATTCTACATTG
SP-HA-Xho I F	CCGCTCGAGCGGATGAAAAAAAAG
HA-Xba I R	GCTCTAGAGCTTAAATGCAAATTCTGC
Pz F	AAGTCGCGTGGCGCGCCAGTCTTATAACTATACTGACAATA
Ter R	GAAATGATAGGCGCGCCATAAGCAAAAGGCAGCTGAT
pgsA F	ATGAAAAAAGAACTGAGCTTTCATGAAAAGCTGC
pgsA R	TGAACCACCACCACCGGAT
GFP-CM F	ATGAAAAAAAAGATTATCTCAGCTATTTTAA
GFP-CM R	TTATTTTATTCGTAGATACTGACCAATTAAAATAGTATCGC
8148 F	CCTGCCCCGTTAGTTGAAGAAGG
8148 R	GCTTTATCAACTGCTGCTTTTTGGCT
BmpA-HA1(1)F	AAATAAATTATAAGGAGGCACTCACATGAAAAAACGCGTAATCGCAGTTAG
BmpA-HA1(1)R	AAATTTGATCTGAACCACCACCACCGGAT
BmpA-HA1(2)F	TGGTGGTTCAGATCAAATTTGCATTGGCTACCATGC
BmpA-HA1(2)R	GTTTTCTAATTTTGGTTCAAAGAATTAAATACAAATTCTACATTGTAATGATCCATTTG
HA1-cA(1)F	ATAAATTATAAGGAGGCACTCACATGAAAAAAAAGATTATCTCAGCTATTTTAATGTCT
HA1-cA(1)R	CTCCTCCTCCAATACAAATTCTACATTGTAATGATCCATTTGAACACATC
HA1-cA(2)F	AATTTGTATTGGAGGAGGAGGATCCGGTGGT
HA1-cA(2)R	GGTTTTCTAATTTTGGTTCAAAGAATTATTTTATTCGTAGATACTGACCAATTAAAATA
SPHA1-8148 F	TAAATTATAAGGAGGCACTCACATGAAAAAAAAGATTATCTCAGCTATTTTAATGTCTA
SPHA1-8148 R	GTTTTCTAATTTTGGTTCAAAGAATTAAATACAAATTCTACATTGTAATGATCCATTTG
SP-GFP F	GTTTACGCTCGTAAAGGCGAAGAGCTGTTCAC
Nco I-pgsA F	AAATAAATTATAAGGAGGCACTCACATGAAAAAAGAACTGAGCTTTCATGAAAAGCT
Nco I-BmpA F	AAATAAATTATAAGGAGGCACTCACATGAAAAAACGCGTAATCGCAGTTAG

组别 Group	剂量 Dose	试验动物/只 Animal numbers
PBS组	100 μL·只^-1	5
NZB-pNZ8148-HA1免疫组	1.0×10¹¹ CFU·只^-1	5
NZB-pNZ8148-BmpA-HA1免疫组	1.0×10¹¹ CFU·只^-1	5
NZB-pNZ8148-HA1-cA免疫组	1.0×10¹¹ CFU·只^-1	5
NZB-HA1-pNZ8148-BmpA-HA1免疫组	1.0×10¹¹ CFU·只^-1	5
NZB-HA1-pNZ8148-HA1-cA免疫组	1.0×10¹¹ CFU·只^-1	5

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Construction of Recombinant Lactococcus lactis Inducible Expressing HA Protein of H5N1 Subtype Avian Influenza Virus and Analysis of Its Immunogenicity in Ducks

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