Effect of Deletion of Genes Involved in Lipopolysaccharide Core and O-Antigen Synthesis on Virulence and Immunogenicity of Salmonella enterica Serovar Typhimurium
Effect of Deletion of Genes Involved in Lipopolysaccharide Core and O-Antigen Synthesis on Virulence and Immunogenicity of Salmonella enterica Serovar Typhimurium
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DOI：
10.1128/iai.05398-11
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发表时间：
2011-10-01
影响因子：
3.1
通讯作者：
Curtiss, Roy, III
中科院分区：
文献类型：
--
作者：
Kong, Qingke;Yang, Jiseon;Curtiss, Roy, III
内毒素(LPS)是鼠伤寒沙门氏菌的主要毒力因子，由类脂A、核心低聚糖(C-OS)和O-抗原多糖(O-PS)组成。虽然参与核心和O-抗原合成的基因产物的功能已被阐明，但去除O-抗原和核心糖对鼠伤寒沙门氏菌毒力和免疫原性的影响尚未有系统的研究。我们在野生型鼠伤寒沙门氏菌中引入了WAAG(RfaG)、WAAI(RFAI)、rfaH、waaJ(RfaJ)、WBAP(RfbP)、Waal(RfaL)或wzy(RFC)的非极性、明确的缺失突变。确定了内毒素的结构，并对每个突变体的体内外特性进行了分析。与野生型亲本相比，所有突变体在口服给BALB/c小鼠时都显著减弱，并且对宿主组织的侵袭性较小。特别是，具有Delta Waag和Delta WAAI突变的菌株在Peyer‘s斑块和肝脏的定植方面存在缺陷。当Delta WAAI突变体经鼻腔给药时，这一缺陷可以部分克服。在提供肺炎球菌抗原PSPA的减毒疫苗株的背景下，所有测试的突变都导致对PSPA和沙门氏菌抗原的免疫反应降低。我们的结果表明，不可逆地截断外核不是开发口服活沙门氏菌疫苗的可行选择，而保留一个O抗原单位的wzy突变体足以通过口服、鼻腔或腹腔给药途径刺激对同源或异种抗原的最佳保护性免疫。
Lipopolysaccharide (LPS) is a major virulence factor of Salmonella enterica serovar Typhimurium and is composed of lipid A, core oligosaccharide (C-OS), and O-antigen polysaccharide (O-PS). While the functions of the gene products involved in synthesis of core and O-antigen have been elucidated, the effect of removing O-antigen and core sugars on the virulence and immunogenicity of Salmonella enterica serovar Typhimurium has not been systematically studied. We introduced nonpolar, defined deletion mutations in waaG (rfaG), waaI (rfaI), rfaH, waaJ (rfaJ), wbaP (rfbP), waaL (rfaL), or wzy (rfc) into wild-type S. Typhimurium. The LPS structure was confirmed, and a number of in vitro and in vivo properties of each mutant were analyzed. All mutants were significantly attenuated compared to the wild-type parent when administered orally to BALB/c mice and were less invasive in host tissues. Strains with Delta waaG and Delta waaI mutations, in particular, were deficient in colonization of Peyer's patches and liver. This deficiency could be partially overcome in the Delta waaI mutant when it was administered intranasally. In the context of an attenuated vaccine strain delivering the pneumococcal antigen PspA, all of the mutations tested resulted in reduced immune responses against PspA and Salmonella antigens. Our results indicate that nonreversible truncation of the outer core is not a viable option for developing a live oral Salmonella vaccine, while a wzy mutant that retains one O-antigen unit is adequate for stimulating the optimal protective immunity to homologous or heterologous antigens by oral, intranasal, or intraperitoneal routes of administration.