The Role of BACH2 in T Cells in Experimental Malaria Caused by Plasmodium chabaudi chabaudi AS.

BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2 (BACH2) is a transcription factor best known for its role in B cell development. More recently, it has been associated with T cell functions in inflammatory diseases, and has been proposed as a master transcriptional regulator within the T cell compartment. In this study, we employed T cell-specific Bach2-deficient (B6.Bach2ΔT ) mice to examine the role of this transcription factor in CD4+ T cell functions in vitro and in mice infected with Plasmodium chabaudi AS. We found that under CD4+ T cell polarizing conditions in vitro, Th2, and Th17 helper cell subsets were more active in the absence of Bach2 expression. In mice infected with P. chabaudi AS, although the absence of Bach2 expression by T cells had no effect on blood parasitemia or disease pathology, we found reduced expansion of CD4+ T cells in B6.Bach2ΔT mice, compared with littermate controls. Despite this reduction, we observed increased frequencies of Tbet+ IFNγ+ CD4+ (Th1) cells and IL-10-producing Th1 (Tr1) cells in mice lacking Bach2 expression by T cells. Studies in mixed bone marrow chimeric mice revealed T cell intrinsic effects of BACH2 on hematopoietic cell development, and in particular, the generation of CD4+ and CD8+ T cell subsets. Furthermore, T cell intrinsic BACH2 was needed for efficient expansion of CD4+ T cells during experimental malaria in this immunological setting. We also examined the response of B6.Bach2ΔT mice to a second protozoan parasitic challenge with Leishmania donovani and found similar effects on disease outcome and T cell responses. Together, our findings provide new insights into the role of BACH2 in CD4+ T cell activation during experimental malaria, and highlight an important role for this transcription factor in the development and expansion of T cells under homeostatic conditions, as well as establishing the composition of the effector CD4+ T cell compartment during infection.

Spatiotemporal requirements for IRF7 in mediating type I IFN-dependent susceptibility to blood-stage Plasmodium infection.

Type I IFN signaling suppresses splenic T helper 1 (Th1) responses during blood-stage Plasmodium berghei ANKA (PbA) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. Interferon regulatory factor 7 (IRF7) is considered to be a master regulator of type I IFN responses. Here, we assessed IRF7 for its roles during lethal PbA infection and nonlethal Plasmodium chabaudi chabaudi AS (PcAS) infection as two distinct models of blood-stage malaria. We found that IRF7 was not essential for tissue accumulation of parasites, cerebral symptoms, or brain pathology. Using timed administration of anti-IFNAR1 mAb, we show that late IFNAR1 signaling promotes fatal disease via IRF7-independent mechanisms. Despite this, IRF7 significantly impaired early splenic Th1 responses and limited control of parasitemia during PbA infection.  Finally, IRF7 also suppressed antiparasitic immunity and Th1 responses during nonlethal PcAS infection. Together, our data support a model in which IRF7 suppresses antiparasitic immunity in the spleen, while IFNAR1-mediated, but IRF7-independent, signaling contributes to pathology in the brain during experimental blood-stage malaria.

Plasmodium berghei ANKA (PbA) infection of C57BL/6J mice: a model of severe malaria.

The term "severe malaria" refers to a wide spectrum of syndromes in Plasmodium-infected humans including cerebral malaria (CM), respiratory distress, severe anemia, liver dysfunction, and hypoglycemia. Mouse models have been employed to further our understanding of the pathology and immune responses that occur during Plasmodium infection. Evidence of brain, liver, lung, and spleen pathology, as well as anemia and tissue-sequestration of parasites, has been reported in various strains of inbred mice. While no single mouse model mimics all the various clinical manifestations of severe malaria in humans, here we describe a detailed protocol for Plasmodium berghei ANKA infection of C57BL/6J mice. For many years, this model has been referred to as "experimental cerebral malaria," but in fact recapitulates many of the symptoms and pathologies observed in most severe malaria syndromes.

Type I interferons suppress CD4⁺ T-cell-dependent parasite control during blood-stage Plasmodium infection.

During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+) T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+) T cells. Expression analysis revealed that the transcriptional signature of CD4(+) T cells from PbA-infected mice was dominated by type I IFN (IFN-I) and IFN-γ-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-α protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+) T-bet(+) T-cell-derived IFN-γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio-sensitive, haematopoietic cells, but did not suppress CD4(+) T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-γ production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+) T-cell-mediated parasite control.