Type I interferons suppress CD4⁺ T-cell-dependent parasite control during blood-stage Plasmodium infection
Ashraful Haque1, Shannon E Best, Anne Ammerdorffer
1Immunology and Infection Laboratory, Queensland Institute of Medical Research and The Australian Centre for Vaccine Development, Herston, QLD, Australia. ashraful.haque@qimr.edu.au
Abstract:
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.
Insights
Type I interferon (IFN-I) signaling impairs T-cell control of malaria parasites during blood-stage Plasmodium infection. This pathway suppresses crucial IFN-γ production, hindering parasite clearance and exacerbating disease severity.
Area of Science:
- Immunology
- Infectious Diseases
- Malariology
Background:
- Blood-stage Plasmodium infection involves rapid red blood cell invasion, often preceding robust immune responses.
- CD4(+) T cells in Plasmodium berghei ANKA (PbA)-infected mice primarily aided pathogenic CD8(+) T cells rather than controlling parasite numbers.
- Transcriptional analysis of CD4(+) T cells revealed significant type I interferon (IFN-I) and IFN-γ signaling pathway gene expression.
Purpose of the Study:
- To investigate the role of IFN-I signaling in blood-stage Plasmodium infection.
- To determine the impact of IFN-I on T cell responses and parasite control.
- To elucidate the cellular mechanisms by which IFN-I exerts its effects during malaria.
Main Methods:
- Observation of IFN-α protein production in infected mouse spleens.
- Analysis of parasite burdens and neurological symptoms in IFN-I signaling-deficient mice.
- Experiments using bone marrow (BM) chimeric mice to assess cell-type specific IFN-I signaling.
- Assessment of IFN-γ production and parasite control in mice infected with Plasmodium chabaudi.
Main Results:
- IFN-α protein was detected in the spleen within the first 2 days of PbA infection.
- Mice lacking IFN-I signaling exhibited reduced parasite loads and were protected from fatal neurological symptoms.
- IFN-I significantly inhibited IFN-γ production by CD4(+) T-bet(+) T cells, preventing effective parasite control.
- IFN-I signaling acted on radio-sensitive hematopoietic cells, not directly on CD4(+) T cells.
- IFN-I suppressed IFN-γ production and impaired parasite control in Plasmodium chabaudi-infected mice.
Conclusions:
- IFN-I signaling plays a critical, detrimental role during blood-stage Plasmodium infection.
- IFN-I suppresses CD4(+) T cell-mediated parasite control by inhibiting IFN-γ production.
- This study identifies a novel regulatory pathway where IFN-I suppresses anti-parasitic immunity, impacting malaria pathogenesis.
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