IgG Responses to Porins and Lipopolysaccharide within an Outer Membrane-Based Vaccine against Nontyphoidal Salmonella Develop at Discordant Rates.
IgG Responses to Porins and Lipopolysaccharide within an Outer Membrane-Based Vaccine against Nontyphoidal Salmonella Develop at Discordant Rates.
复制标题
DOI：
10.1128/mbio.02379-17
复制
发表时间：
2018-03-06
期刊：
影响因子：
6.4
通讯作者：
Cunningham AF
中科院分区：
文献类型：
--
作者：
Schager AE;Dominguez-Medina CC;Necchi F;Micoli F;Goh YS;Goodall M;Flores-Langarica A;Bobat S;Cook CNL;Arcuri M;Marini A;King LDW;Morris FC;Anderson G;Toellner KM;Henderson IR;López-Macías C;MacLennan CA;Cunningham AF
接种疫苗或自然感染革兰氏阴性菌（如侵袭性肠炎沙门氏菌血清型鼠伤寒沙门氏菌）后获得的抗体可预防疾病。利用革兰氏阴性菌自然脱落的外膜囊泡进行免疫接种，由于囊泡内的抗原保持其自然的构象和取向，因此正在研究其预防许多感染的潜力。通过基因修饰可以增强脱落，产生的颗粒，即膜抗原通用模块（GMMA），不仅具有作为疫苗的潜力，而且可以促进研究b细胞对细菌抗原的反应。本研究表明，鼠伤寒沙门氏菌GMMA （STmGMMA）免疫应答提供b细胞依赖性保护，并诱导针对两种免疫优势抗原，脂多糖（LPS）和孔蛋白的抗体。脂多糖O抗原（O- ag）抗体显著增强脾脏的保护作用，但这种作用在肝脏中不太明显。引人注目的是，IgG对LPS和孔蛋白的反应具有不同的动力学。在免疫后的第一周，除IgG1外，所有IgG同型均与t细胞无关的b1细胞相关，诱导其进入孔蛋白，但不诱导LPS。相反，这两种抗原的IgG1的产生是延迟的，并且依赖于T细胞。然而，1个月后，骨髓中针对孔蛋白或LPS分泌IgG的细胞以相似的频率存在。出乎意料的是，接种o - ag缺陷STmGMMA并没有显著增强抗孔蛋白应答。因此，在同一复合体内，IgG向所有抗原的转换并不是同步发生的，因此IgG向单一组分转换的速率并不一定反映其在抗原复合体内的频率。疫苗挽救了数百万人的生命，但有些感染却没有疫苗。这包括某些类型的沙门氏菌感染，每年导致数十万人死亡。我们展示了一种名为GMMA的新型疫苗是如何通过诱导宿主蛋白（抗体）特异性识别细菌成分（抗原）来保护小鼠免受感染的，这种疫苗是由沙门氏菌细胞壁脱落的水泡制成的。在GMMA中，针对抗原的IgG抗体的产生速度有不同的动力学。然而，抗体对GMMA的反应持续存在，并可能为那些需要它的人提供长期的保护。这些结果有助于展示抗体对细菌抗原的反应是如何产生的，以及像GMMA这样的疫苗是如何起作用并帮助预防感染的。
Antibodies acquired after vaccination or natural infection with Gram-negative bacteria, such as invasive Salmonella enterica serovar Typhimurium, can protect against disease. Immunization with naturally shed outer membrane vesicles from Gram-negative bacteria is being studied for its potential to protect against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification, and the resulting particles, generalized modules for membrane antigens (GMMA), not only offer potential as vaccines but also can facilitate the study of B-cell responses to bacterial antigens. Here we show that the response to immunization with GMMA from S. Typhimurium (STmGMMA) provides B-cell-dependent protection and induces antibodies to two immunodominant antigens, lipopolysaccharide (LPS) and porins. Antibodies to LPS O antigen (O-Ag) markedly enhance protection in the spleen, but this effect is less marked in the liver. Strikingly, IgG responses to LPS and porins develop with distinct kinetics. In the first week after immunization, there is a dramatic T-cell-independent B1b-cell-associated induction of all IgG isotypes, except IgG1, to porins but not to LPS. In contrast, production of IgG1 to either antigen was delayed and T cell dependent. Nevertheless, after 1 month, cells in the bone marrow secreting IgG against porins or LPS were present at a similar frequency. Unexpectedly, immunization with O-Ag-deficient STmGMMA did not substantially enhance the anti-porin response. Therefore, IgG switching to all antigens does not develop synchronously within the same complex and so the rate of IgG switching to a single component does not necessarily reflect its frequency within the antigenic complex. Vaccines save millions of lives, yet for some infections there are none. This includes some types of Salmonella infections, killing hundreds of thousands of people annually. We show how a new type of vaccine, called GMMA, that is made from blebs shed from the Salmonella cell wall, works to protect against infection in mice by inducing host proteins (antibodies) specifically recognizing bacterial components (antigens). The rate of development of IgG antibody to antigens within GMMA occurred with different kinetics. However, the antibody response to GMMA persists and is likely to provide prolonged protection for those who need it. These results help show how antibody responses to bacterial antigens develop and how vaccines like GMMA can work and help prevent infection.