利用大蜡螟幼虫和小鼠感染模型筛选猪链球菌血清2、3和9型三价灭活疫苗候选菌株

doi:10.11843/j.issn.0366-6964.2024.09.032

畜牧兽医学报 ›› 2024, Vol. 55 ›› Issue (9): 4077-4090.doi: 10.11843/j.issn.0366-6964.2024.09.032

利用大蜡螟幼虫和小鼠感染模型筛选猪链球菌血清2、3和9型三价灭活疫苗候选菌株

朋璐(), 张衡(), 庞思琪, 乔竹林, 张小芬, 谭臣, 宋云峰, 周锐, 黎璐*()

华中农业大学动物医学院, 农业微生物资源发掘与利用全国重点实验室, 生猪健康养殖省部共建协同创新中心, 武汉 430070

收稿日期:2023-11-20 出版日期:2024-09-23 发布日期:2024-09-27
通讯作者: 黎璐 E-mail:penglu1998@webmail.hzau.edu.cn;zhangheng666@webmail.hzau.edu.cn;lilu@mail.hzau.edu.cn
作者简介:朋璐(1998-), 女, 安徽安庆人, 博士, 主要从事动物传染病研究, E-mail: penglu1998@webmail.hzau.edu.cn
张衡(1996-), 男, 湖北武汉人, 硕士, 主要从事动物传染病研究, E-mail: zhangheng666@webmail.hzau.edu.cn
第一联系人：
朋璐和张衡为同等贡献作者
基金资助:
国家重点研发计划(2021YFD1800404)

Screening of Trivalent Inactivated Vaccine Candidate Strains of Streptococcus suis Serotype 2, 3 and 9 Using Galleria mellonella and Mice Infection Models

Lu PENG(), Heng ZHANG(), Siqi PANG, Zhulin QIAO, Xiaofen ZHANG, Chen TAN, Yunfeng SONG, Rui ZHOU, Lu LI*()

National Key Laboratory of Agricultural Microbiology, The Cooperative Innovation Center for Sustainable Pig Production Co-sponsored by Province and Ministry, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China

Received:2023-11-20 Online:2024-09-23 Published:2024-09-27
Contact: Lu LI E-mail:penglu1998@webmail.hzau.edu.cn;zhangheng666@webmail.hzau.edu.cn;lilu@mail.hzau.edu.cn

摘要/Abstract

摘要：

旨在评估临床分离的猪链球菌血清2、3、9型强毒株制备的三价灭活疫苗对小鼠的免疫保护效果。使用大蜡螟幼虫感染模型和小鼠感染模型, 从临床分离的猪链球菌中筛选出血清2、3和9型强毒株各1株(SS1803、SS1803024、SS1696), 检测其生长曲线和毒力因子。将菌株分别灭活及混合灭活后与佐剂混合, 用4×10⁷ CFU、8×10⁷ CFU SS1803、2×10⁸ CFU、5×10⁸ CFU SS1803024、1×10⁸ CFU、5×10⁸ CFU SS1696及三价灭活苗(2×10⁷ CFU SS1803+1.5×10⁸ CFU SS1803024+3×10⁷ CFU SS1696)分别对BALB/c小鼠进行两轮免疫, 采集血清检测特异性抗体水平, 分别用3种菌株致死剂量攻毒后观察小鼠免疫保护率, 同时用亚致死剂量攻毒三价苗免疫组, 测定小鼠血、脑、肺、脾的组织载菌量和细胞因子IL-6、IL-12水平, 并观察脑、肺、脾、肾中的组织病理变化。结果显示: 3株疫苗候选菌株的毒力基因鉴定分别为SS1803: gapdh⁺/sly⁺/fbps⁺/orf2⁺/mrp^-/89K^-/gdh⁺/epf⁺, SS1803024: gapdh⁺/sly⁺/fbps⁺/orf2⁺/mrp^-/89K^-/gdh⁺/epf^-, SS1696: gapdh⁺/sly^-/fbps⁺/orf2⁺/mrp^-/89K^-/gdh⁺/epf^-。单价和三价疫苗免疫组均能产生对应免疫血清型的IgG抗体, 以产生IgG1型抗体为主。三价疫苗免疫组能对2、3、9型3个菌株攻毒分别提供83.3%、66.7%和66.7%的保护率, 能显著降低感染后小鼠组织中的载菌量, 降低血清炎性因子水平和组织病变程度。本研究筛选临床流行率高的2、3、9型强毒株, 联合制备三价灭活疫苗, 能够对小鼠提供良好的免疫保护力, 为猪链球菌多价疫苗的研发提供新的材料。

关键词: 猪链球菌, 疫苗候选菌株, 三价灭活疫苗, 免疫保护效果

Abstract:

The aim was to evaluate the immune protective effect of a trivalent inactivated vaccine prepared from virulent strains of clinically isolated Streptococcus suis serotype 2, 3 and 9 on mice. One virulent strain each of S. suis serotype 2, 3 and 9 were screened from clinical isolates using Galleria mellonella and mice infection models(SS1803, SS1803024, SS1696), and the growth curves and virulence genes were tested. The strains were separately inactivated and mixed inactivated and mixed with adjuvants. 4×10⁷ CFU, 8×10⁷ CFU SS1803, 2×10⁸ CFU, 5×10⁸ CFU SS1803024, 1×10⁸ CFU, 5×10⁸ CFU SS1696, and trivalent inactivated vaccine (2×10⁷ CFU SS1803+1.5×10⁸ CFU SS1803024+3×10⁷ CFU SS1696) were used to immune the BALB/c mice in two rounds, serum was collected to detect the levels of specific antibodies and the immune protection rates of the mice were observed after challenge with lethal doses of the three strains respectively. Then, a sub-lethal dose were used to challenge the trivalent immunized group, the bacterial loads in blood, brain, lung and spleen and the levels of cytokines IL-6 and IL-12 of mice were measured, and the histopathological changes in brain, lung, spleen and kidney were also observed. The virulence genes of the three vaccine candidate strains were identified as: SS1803: gapdh⁺/sly⁺/fbps⁺/orf2⁺/mrp^-/89K^-/gdh⁺/epf⁺, SS1803024: gapdh⁺/sly⁺/fbps⁺/orf2⁺/mrp^-/89K^-/gdh⁺/epf^-, SS1696: gapdh⁺/sly^-/fbps⁺/orf2⁺/mrp^-/89K^-/gdh⁺/epf^-. Both monovalent and trivalent vaccine immune groups induced IgG antibodies corresponding to the immunized serotypes, with the production of IgG1 antibodies predominating. The trivalent group provided 83.3%, 66.7% and 66.7% protection against serotype 2, 3 and 9 strains, respectively. It also effectively reduced the bacterial loads in the tissues, and reduced the levels of serum inflammatory factors and the degree of tissue lesions of mice after infection. In this study, highly virulent strains of serotype 2, 3 and 9 with high clinical prevalence were screened. Trivalent inactivated vaccine were prepared, which provided good immune protection in mice challenge model. These studies provided new materials for the development of multivalent vaccine of Streptococcus suis.

Key words: Streptococcus suis, vaccine candidate strains, trivalent inactivated vaccine, immune protective effect

中图分类号:

S852.611

朋璐, 张衡, 庞思琪, 乔竹林, 张小芬, 谭臣, 宋云峰, 周锐, 黎璐. 利用大蜡螟幼虫和小鼠感染模型筛选猪链球菌血清2、3和9型三价灭活疫苗候选菌株[J]. 畜牧兽医学报, 2024, 55(9): 4077-4090.

Lu PENG, Heng ZHANG, Siqi PANG, Zhulin QIAO, Xiaofen ZHANG, Chen TAN, Yunfeng SONG, Rui ZHOU, Lu LI. Screening of Trivalent Inactivated Vaccine Candidate Strains of Streptococcus suis Serotype 2, 3 and 9 Using Galleria mellonella and Mice Infection Models[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(9): 4077-4090.

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引物Primers	引物序列(5′→3′) Sequence	产物大小/bp Product
cps2I-F	TTCGTATTAACTTACTTGGCGT	363
cps2I-R	TAAATCCCCATATGCCAAATCC
cps3L-F	ACATCCATTGCAGGAGTAGT	210
cps3L-R	TGCAGTTCCAAAATTCTTCGT
cps9J-F	TCCCTTTAATTTCACAGGCAAT	409
cps9J-R	CTGTCAAAGAATTGAATCCCAC
gapdh-F	CACACTTGTTGAAATATGACAC	571
gapdh-R	AGCACCGTCAAGTTTACC
sly-F	GCAGAAGGGACAACTGTAGAAG	443
sly-R	GCACTGCTATTATGGACTGTTGA
fbps-F	CAAGGTTTGGGTCGGGATA	720
fbps-R	CCCGTCTGTTGCCAAGTAA
orf2-F	CAAGTGTATGTGGATGGG	858
orf2-R	ATCCAGTTGACACGTGCA
mrp-F	GGTATACCTTGCTGGTACGGTTC	532
mrp-R	AGTCTCTACAGCTGTAGCTGG
89K-F	GATATCGCCACTATGGTATC	720
89K-R	GATTGTGGACCATGCTCTTTAG
gdh-F	GCAGCGYAYYCYGYCAAACG	688
gdh-R	CCATGGACAGATAAAGATGG
epf-F	ACAAAGGCGTAGGTTCAATC	269
epf-R	CGGCATCAAGAATGTCTTTG

组别Group	免疫剂量Immune dose	数量Quantity	免疫方式Vaccination method	攻毒菌株/剂量Challenge strain/dose	攻毒方式Challenge method
SS1803免疫组 SS1803	4×10⁷ CFU	6	肌肉注射Intramuscular injection	SS1803: 5×10⁷ CFU	腹腔注射Intraperitoneal injection
SS1803免疫组 SS1803	8×10⁷ CFU	6	肌肉注射Intramuscular injection	SS1803: 5×10⁷ CFU	腹腔注射Intraperitoneal injection
SS1803024免疫组 SS1803024	2×10⁸ CFU	6	肌肉注射Intramuscular injection	SS1803024: 1.7×10⁸ CFU	腹腔注射Intraperitoneal injection
SS1803024免疫组 SS1803024	5×10⁸ CFU	6	肌肉注射Intramuscular injection	SS1803024: 1.7×10⁸ CFU	腹腔注射Intraperitoneal injection
SS1696免疫组 SS1696	1×10⁸ CFU	6	肌肉注射Intramuscular injection	SS1696: 1.5×10⁷ CFU	腹腔注射Intraperitoneal injection
SS1696免疫组 SS1696	5×10⁸ CFU	6	肌肉注射Intramuscular injection	SS1696: 1.5×10⁷ CFU	腹腔注射Intraperitoneal injection
三价苗免疫组 TIV	2×10⁷ CFU SS1803+1.5×10⁸ CFU SS1803024+3×10⁷ CFU SS1696	18	肌肉注射Intramuscular injection	SS1803: 5×10⁷ CFU SS1803024: 1.7×10⁸ CFU SS1696: 1.5×10⁷ CFU	腹腔注射Intraperitoneal injection
阴性对照组 Negative	PBS	18	肌肉注射Intramuscular injection	SS1803: 5×10⁷ CFU SS1803024: 1.7×10⁸ CFU SS1696: 1.5×10⁷ CFU	腹腔注射Intraperitoneal injection

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利用大蜡螟幼虫和小鼠感染模型筛选猪链球菌血清2、3和9型三价灭活疫苗候选菌株

Screening of Trivalent Inactivated Vaccine Candidate Strains of Streptococcus suis Serotype 2, 3 and 9 Using Galleria mellonella and Mice Infection Models

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血清3型菌株Serotype 3 strains	第一轮死亡率(n=10) Mortality rate of first round experiment	第二轮死亡率(n=10) Mortality rate of second round experiment	血清9型菌株Serotype 9 strains	第一轮死亡率(n=10) Mortality rate of first round experiment	第二轮死亡率(n=10) Mortality rate of second round experiment
SS1761	60	80	SS1802036	60	50
SS1804125	100	60	SS1807065	80	80
SS1730	10	10	SS1823	30	40
SS1767	20	20	SS1805031	90	70
SS1766	30	40	SS1805032	60	40
SS1968	10	10	SS1804104	90	90
SS1803024	100	60	SS1804097	30	20
SS1803025	70	60	SS1407	0	10
SS2214	30	10	SS1904022	10	10
SS1703	40	30	SS1681	40	20
SS1804072	40	10	SS1696	80	80
SS1808002	30	20	SS1697	70	60
生理盐水组Normal saline group	0	0	SS1807038	40	20
生理盐水组Normal saline group	0	0	SS1807035	80	80
空白对照组Blank control group	0	0	SS1807091	30	30
空白对照组Blank control group	0	0	SS1807090	30	0
			生理盐水组Normal saline group	0	0
			空白对照组Blank control group	0	0