Abstract
Cerebral malaria (CM) is one of the most severe complications of Plasmodium falciparum 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 Plasmodium berghei 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 Plasmodium infections, for modulating the B cell compartment and eventually suppressing memory CD8+ T cell reactivation to establish infection-induced resistance to ECM.
Highlights
Malaria remains one of the most prevalent and severe diseases in the world, responsible for 445,000 deaths, principally in Sub Saharan Africa, in 2016 [1]
We show that infection-induced resistance to experimental cerebral malaria (ECM) is associated with the significant expansion of atypical B cell populations and repression of memory CD8+ T cell reactivation, and that this protection is abrogated in mice unable to produce secreted antibody, or undergo class switching
To recapitulate the natural repeated Plasmodium falciparum infections experienced by humans in endemic regions [10] we adapted the established Plasmodium berghei ANKA (PbA) model of ECM (Figure 1)
Summary
Malaria remains one of the most prevalent and severe diseases in the world, responsible for 445,000 deaths, principally in Sub Saharan Africa, in 2016 [1]. Children under 5 years of age are disproportionally susceptible to cerebral malaria whereas older children and adults, despite often harboring very high parasite burdens, rarely develop severe disease [4]. Adults remain susceptible to severe malarial disease in non-endemic malarial areas and in regions of unstable transmission [4]. Despite substantial research, the nature, and identity of the immune responses that develop following natural repeated exposure to prevent cerebral malaria are poorly understood [5,6,7,8,9]
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