Roberts M, Bacon A, Li J, Chatfield S
Department of Veterinary Pathology, Glasgow University Veterinary School, Glasgow G61 1QH, United Kingdom.
Infect Immun. 1999 Aug;67(8):3810-5. doi: 10.1128/IAI.67.8.3810-3815.1999.
We have investigated the effect of preexisting immunity to homologous (Salmonella typhimurium) or heterologous (S. dublin) serotypes of Salmonella on the ability of an attenuated S. typhimurium aroA aroD vector (BRD509) to immunize mice against the heterologous antigen fragment C (FrgC). We studied two strains, BRD847 and BRD937, expressing FrgC carried on plasmids that differ only with respect to the promoter controlling FrgC expression, the nirB promoter in the case of BRD847 and the htrA promoter in the case of BRD937. Mice were preimmunized orally with S. typhimurium BRD509, S. dublin aroA aroD (BRD620), or saline. Forty-four days later, they were immunized orally with BRD847 or BRD937. Prior immunity to S. typhimurium severely depressed the serum immunoglobulin G (IgG) and IgA anti-FrgC response in both BRD847- and BRD937-immunized mice. Mice with existing immunity to S. dublin also had lower IgG anti-FrgC geometric mean titers (GMTs) than did mice preimmunized with saline, but this difference was significant only in the case of mice immunized with BRD937. However, in nonimmune mice or in mice preimmunized with S. typhimurium or S. dublin, the anti-FrgC IgG GMTs were always higher in mice in the BRD937 groups than in the equivalent BRD847 groups. This is reflected in the effect of prior immunity on the ability of oral immunization with BRD847 or BRD937 to protect mice from challenge with a lethal dose of tetanus toxin. All of the mice preimmunized with saline and then immunized with BRD847 or BRD937 survived challenge. Only 20% of the animals immunized with BRD847 and 60% of the mice in the BRD937 group survived tetanus toxin challenge if they were preimmunized with BRD509. Preexisting immunity to S. dublin did not affect the ability of BRD937 to immunize mice against tetanus, but it did reduce the efficiency of BRD847: only 60% percent of the mice survived challenge. The intestinal secretory IgA responses to FrgC were very similar in the BRD847 and BRD937 groups. Prior immunity did depress the IgA anti-FrgC titers but only significantly so in the mice preimmunized with BRD509. These results show that preexisting Salmonella immunity, particularly to homologous serotypes, can severely compromise the ability of live Salmonella vectors to deliver heterologous antigens to the mammalian immune system. However, the results also indicate that this may be overcome by the design of more powerful in vivo expression systems.
我们研究了对同源（鼠伤寒沙门氏菌）或异源（都柏林沙门氏菌）血清型沙门氏菌的预先存在的免疫力，对减毒鼠伤寒沙门氏菌aroA aroD载体（BRD509）免疫小鼠抵抗异源抗原片段C（FrgC）能力的影响。我们研究了两个菌株，BRD847和BRD937，它们表达的FrgC携带在质粒上，这些质粒仅在控制FrgC表达的启动子方面有所不同，BRD847的情况是nirB启动子，BRD937的情况是htrA启动子。小鼠经口用鼠伤寒沙门氏菌BRD509、都柏林沙门氏菌aroA aroD（BRD620）或生理盐水进行预先免疫。44天后，它们经口用BRD847或BRD937进行免疫。对鼠伤寒沙门氏菌的预先免疫严重抑制了用BRD847和BRD937免疫的小鼠血清免疫球蛋白G（IgG）和IgA抗FrgC反应。对都柏林沙门氏菌有现有免疫力的小鼠，其IgG抗FrgC几何平均滴度（GMT）也低于用生理盐水预先免疫的小鼠，但这种差异仅在用BRD937免疫的小鼠中显著。然而，在未免疫的小鼠或用鼠伤寒沙门氏菌或都柏林沙门氏菌预先免疫的小鼠中，BRD937组小鼠的抗FrgC IgG GMT总是高于相应的BRD847组。这反映在预先免疫对用BRD847或BRD937经口免疫保护小鼠免受致死剂量破伤风毒素攻击能力的影响上。所有用生理盐水预先免疫然后用BRD847或BRD937免疫的小鼠在攻击中存活。如果用BRD509预先免疫，用BRD847免疫的动物中只有20%存活，BRD937组小鼠中有60%存活。对都柏林沙门氏菌的预先存在的免疫力不影响BRD937免疫小鼠抵抗破伤风的能力，但确实降低了BRD847的效率：只有60%的小鼠在攻击中存活。BRD847和BRD937组对FrgC的肠道分泌型IgA反应非常相似。预先免疫确实降低了IgA抗FrgC滴度，但仅在用BRD509预先免疫的小鼠中显著降低。这些结果表明，预先存在的沙门氏菌免疫力，特别是对同源血清型的免疫力，可严重损害活沙门氏菌载体向哺乳动物免疫系统递送异源抗原的能力。然而，结果也表明，这可能通过设计更强大的体内表达系统来克服。
