Plasmodium-specific atypical memory B cells are short-lived activated B cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA473982 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7241810_1.fastq.gz | Fastqsanger.gz | |||
| SRR7241810_2.fastq.gz | Fastqsanger.gz | |||
| SRR7241820_1.fastq.gz | Fastqsanger.gz | |||
| SRR7241820_2.fastq.gz | Fastqsanger.gz | |||
| SRR7241811_1.fastq.gz | Fastqsanger.gz |
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Project description:Chronic infections such as HIV, tuberculosis and malaria in humans are associated with the appearance of atypical memory B cells in peripheral blood. It has been suggested that these B cells do not function normally as memory cells, and thus may be responsible for poor acquisition of immunity and maintenance of chronic infections. Studies on these cells in human infections are limited by the lack of accessibility to lymphoid organs, and relevant mouse models would be valuable to investigate their development, functional capacities, and role. To investigate Plasmodium-specific memory B-cell responses during malaria, we generated an immunoglobin heavy chain knock-in mouse with a B-cell receptor that recognizes the merozoite surface protein (MSP)-1 of the rodent malaria parasite, Plasmodium chabaudi. Using this mouse and a P. chabaudi infection initiated by infected mosquito bites we show that antigen-specific B cells with many characteristics of human atypical memory B cells are generated. These cells are immunoglobulin class-switched and express, among others, the cell surface molecules CD11c, CD11b, FCRL5, and some inhibitory receptors including PD1 and LAIR-1, as well as the transcription factor T-bet. Antigen-specific atypical memory B cells are detected side-by-side with classical memory B cells during chronic blood-stage infection. Whereas classical memory B cells persist after complete infection clearance, atypical memory B cells are short-lived and disappear from the spleen at the resolution of chronic infection. Short-lived Plasmodium-specific atypical B cells also appear transiently after immunization with a TLR7/8 ligand and MSP-1. Our data suggest that these atypical memory B cells are not a subset of memory B cells, but rather antigen-experienced activated cells, and part of a normal ongoing response. Their persistence over weeks in malaria and other infections may be a consequence of continued and chronic antigenic stimulation.
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Project description:A subset of atypical memory B cells accumulates in malaria and several infections, autoimmune disorders and aging in both humans and mice. It has been suggested these cells are exhausted long-lived memory B cells, and their accumulation may contribute to poor acquisition of long-lasting immunity to certain chronic infections, such as malaria and HIV. Here, we generated an immunoglobulin heavy chain knock-in mouse with a BCR that recognizes MSP1 of the rodent malaria parasite, Plasmodium chabaudi. In combination with a mosquito-initiated P. chabaudi infection, we show that Plasmodium-specific atypical memory B cells are short-lived and disappear upon natural resolution of chronic infection. These cells show features of activation, proliferation, DNA replication, and plasmablasts. Our data demonstrate that Plasmodium-specific atypical memory B cells are not a subset of long-lived memory B cells, but rather short-lived activated cells, and part of a physiologic ongoing B-cell response.
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Project description:Plasmodium falciparum malaria is a deadly infectious disease for which we have no licensed vaccine. Antibodies confer protection against malaria and individuals exposed to P. falciparum acquire protective antibodies, but only after years of repeated infections. We recently showed that malaria exposure is associated with a large expansion of a population of atypical memory B cells (MBCs) that phenotypically resemble B cell populations expanded in chronic viral infections, including HIV. At present the relationship of atypical MBCs to classical MBCs and their function are not known. We provide evidence that the expressed VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable, indicating the two populations are closely related developmentally. Atypical MBCs can be distinguished by their expression of multiple inhibitory receptors, including Fc receptor-like-5. B cell receptor (BCR) signaling is stunted in atypical MBCs, resulting in impaired Ca2+ mobilization, proliferation and cytokine production. Atypical MBCs do not spontaneously secrete antibodies and cannot be stimulated to differentiate into antibody-secreting cells in vitro. These results suggest that in individuals chronically exposed to malaria, atypical MBCs differentiate from classical MBCs and assume a phenotype refractory to BCR-mediated activation, potentially contributing to the inefficient acquisition of immunity to malaria. Comparison of human atypical B cell versus classical B cell versus naïve B cell.
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Project description:Targeted proTargeted protein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but it has not been systematically explored to what extent it influences target protein degradation. Using mathematical modelling of protein degradation, we demonstrate that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a PROTAC which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required before concluding that a novel agent works as a bone-fide targeted protein degrader. tein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but it has not been systematically explored to what extent it influences target protein degradation. Using mathematical modelling of protein degradation, we demonstrate that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a PROTAC which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required before concluding that a novel agent works as a bone-fide targeted protein degrader.
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Project description:Plasmodium falciparum malaria is a deadly infectious disease for which we have no licensed vaccine. Antibodies confer protection against malaria and individuals exposed to P. falciparum acquire protective antibodies, but only after years of repeated infections. We recently showed that malaria exposure is associated with a large expansion of a population of atypical memory B cells (MBCs) that phenotypically resemble B cell populations expanded in chronic viral infections, including HIV. At present the relationship of atypical MBCs to classical MBCs and their function are not known. We provide evidence that the expressed VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable, indicating the two populations are closely related developmentally. Atypical MBCs can be distinguished by their expression of multiple inhibitory receptors, including Fc receptor-like-5. B cell receptor (BCR) signaling is stunted in atypical MBCs, resulting in impaired Ca2+ mobilization, proliferation and cytokine production. Atypical MBCs do not spontaneously secrete antibodies and cannot be stimulated to differentiate into antibody-secreting cells in vitro. These results suggest that in individuals chronically exposed to malaria, atypical MBCs differentiate from classical MBCs and assume a phenotype refractory to BCR-mediated activation, potentially contributing to the inefficient acquisition of immunity to malaria.
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