Identification of immunodominant CD4+ T cell antigens as vaccine candidates for protection against the infection with Rickettsia typhi and characterization of the Rickettsia typhi-specific CD8+ T cell response

鉴定免疫显性 CD4 T 细胞抗原作为预防伤寒立克次体感染的候选疫苗，并表征伤寒立克次体特异性 CD8 T 细胞反应

• 批准号: 397605306
• 负责人: Dr. Anke Osterloh
• 金额: --
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/397605306?language=en
• 关键词: Identification; immunodominant; CD4+; cell; antigens

During the previous funding period, several antigens of Rickettsia (R.) typhi were identified that have the potential to elicit a CD4+ T cell response, possibly also CD8+ T cell and B cell responses. Most of these antigens have already been cloned and recombinantly expressed. The immunogenicity of these recombinant proteins and their potential use as vaccines will now be tested. Restimulation of CD4+ and CD8+ T cells from R. typhi-infected mice and from the blood of patients will reveal which antigens actually generate a T and B cell response in mouse and human infection with this pathogen. In this context, the T cell response will be analyzed in detail, in particular with regard to the production of cytokines, proliferation and the expression of activation markers. The production of antibodies against these antigens will also be investigated and T and B cell epitopes will be determined. In the context of this work, a possible cross-reactivity towards other rickettsiae, in particular R. prowazekii, will also be examined. For this purpose, mice will be infected with R. prowazekii and the immune response against the recombinant antigens will be analyzed as described. Those antigens, protein fragments or epitopes that are found to be immunodominant in the restimulation of immune cells from infected mice and patients will be further used for immunization of mice and the induction of a T and B cell response will be investigated using the above methods. If immunization is successful, activated CD4+ and CD8+ T cells will be isolated from the immunized mice and adoptively transferred into R. typhi-infected BALB/c CB17 SCID mice that are highly susceptible to infection with this pathogen to test their protective effects. The planned work will reveal which antigens of R. typhi can induce a protective immune response and thus represent candidate vaccines. For the first time, the upcoming funding period will also provide the opportunity to study the response of blood cells from patients, so that their relevance to the human immune response to R. typhi can also be tested. This will give an indication whether an antigen can also be effective as a vaccine candidate in humans. Antigens that are recognized by B cells are further interesting tools for developing new diagnostic methods that are still severely limited. Those antigens could be used for the development of diagnostic by Western blotting and ELISA.

在上一个资助期间，立克次体（R.）发现伤寒杆菌有可能引发CD 4 + T细胞反应，也可能引发CD 8 + T细胞和B细胞反应。这些抗原中的大多数已经被克隆和重组表达。这些重组蛋白的免疫原性和它们作为疫苗的潜在用途现在将被测试。再刺激来自R.从伤寒感染的小鼠和患者血液中提取抗原，将揭示在感染该病原体的小鼠和人中，哪些抗原实际上产生T和B细胞应答。在这种情况下，将详细分析T细胞应答，特别是关于细胞因子的产生、增殖和活化标志物的表达。还将研究针对这些抗原的抗体的产生，并确定T和B细胞表位。在这项工作的背景下，可能的交叉反应，对其他立克次体，特别是R。prowazekii也将受到审查。为此，将小鼠感染R.如所述分析Prowazekii和针对重组抗原的免疫应答。发现在来自感染小鼠和患者的免疫细胞的再刺激中免疫显性的那些抗原、蛋白质片段或表位将进一步用于小鼠的免疫接种，并且将使用上述方法研究T和B细胞应答的诱导。如果免疫成功，则从免疫小鼠中分离活化的CD4+和CD8 + T细胞并过继转移到R.用高度易感该病原体感染的伤寒感染的BALB/c CB17 SCID小鼠来测试它们的保护作用。计划的工作将揭示哪些抗原的R。伤寒可以诱导保护性免疫应答，因此代表候选疫苗。即将到来的资助期还将首次提供研究患者血细胞反应的机会，以便研究它们与人类对R.伤寒也可以测试。这将表明抗原是否也可以作为人类的候选疫苗有效。被B细胞识别的抗原是用于开发新的诊断方法的进一步令人感兴趣的工具，所述新的诊断方法仍然受到严重限制。这些抗原可用于建立Western blotting和ELISA诊断方法。