Faculty of Biology, Medicine and Health, The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom.
Manchester Collaborative Centre for Inflammation Research, The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom.
Front Immunol. 2019 Feb 19;10:248. doi: 10.3389/fimmu.2019.00248. eCollection 2019.
Cerebral malaria (CM) is one of the most severe complications of infection. There is evidence that repeated parasite exposure promotes resistance against CM. However, the immunological basis of this infection-induced resistance remains poorly understood. Here, utilizing the ANKA (PbA) model of experimental cerebral malaria (ECM), we show that three rounds of infection and drug-cure protects against the development of ECM during a subsequent fourth (4X) infection. Exposure-induced resistance was associated with specific suppression of CD8 T cell activation and CTL-related pathways, which corresponded with the development of heterogeneous atypical B cell populations as well as the gradual infection-induced generation and maintenance of high levels of anti-parasite IgG. Mechanistically, transfer of high-titer anti-parasite IgG did not protect 1X infected mice against ECM and depletion of atypical and regulatory B cells during 4X infection failed to abrogate infection-induced resistance to ECM. However, IgMi mice that were unable to produce secreted antibody, or undergo class switching, during the repeated rounds of infection failed to develop resistance against ECM. The failure of infection-induced protection in IgMi mice was associated with impaired development of atypical B cell populations and the inability to suppress pathogenic CD8 T cell responses. Our results, therefore, suggest the importance of anti-parasite antibody responses, gradually acquired, and maintained through repeated infections, for modulating the B cell compartment and eventually suppressing memory CD8 T cell reactivation to establish infection-induced resistance to ECM.
脑型疟疾（CM）是 感染最严重的并发症之一。有证据表明，反复的寄生虫暴露会促进对 CM 的抵抗力。然而，这种感染诱导的抵抗力的免疫学基础仍知之甚少。在这里，我们利用 ANKA（PbA）实验性脑型疟疾（ECM）模型，表明三轮感染和药物治疗可防止在随后的四轮（4X）感染中发生 ECM。暴露诱导的抗性与 CD8 T 细胞活化和 CTL 相关途径的特异性抑制有关，这与异质性非典型 B 细胞群体的发展以及逐渐感染诱导的高寄生虫 IgG 水平的产生和维持相对应。从机制上讲，高滴度抗寄生虫 IgG 的转移并不能保护 1X 感染的小鼠免受 ECM 的侵害，并且在 4X 感染期间耗尽非典型和调节性 B 细胞也不能消除感染诱导的 ECM 抗性。然而，在反复感染过程中无法产生分泌抗体或进行类别转换的 IgMi 小鼠未能发展出对 ECM 的抗性。IgMi 小鼠感染诱导保护的失败与非典型 B 细胞群体的发育受损以及抑制致病性 CD8 T 细胞反应的能力丧失有关。因此，我们的研究结果表明，逐渐获得的抗寄生虫抗体反应并通过反复感染得以维持，对于调节 B 细胞群并最终抑制记忆 CD8 T 细胞的重新激活以建立感染诱导的 ECM 抗性非常重要。
