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In 2022, malaria was responsible for over 600,000 deaths reported in 85 countries. The African region accounted for 95 per cent of these deaths, with 80 per cent reported in children under the age of five who are often susceptible to multiple infections.

While these repeated infections eventually lead to partial immunity, the precise impacts on various immune cells, especially CD4+ T cells, whose role is to orchestrate the body’s immune response and protect the body during malaria infection and re-infection, has been largely unknown.  

In research conducted in experimental mice and published in Nature Communications, researchers applied single-cell and spatial transcriptomics, combined with machine learning methods, to the spleen, a critical organ in the immune response, to watch CD4+ T cells as they responded during re-infection with malaria parasites.

Spatial transcriptomics, also known as tissue genomics, allows scientists to map cells in great detail within body tissue, and revealed here that CD4+ T cells occupied very distinct areas of this immune organ before re-infection.

University of Melbourne’s Associate Professor Ashraful Haque, Laboratory Head at the Doherty Institute and senior author of the study, said they found some CD4+ T cells responding vigorously during re-infection, while in contrast, others seemed to do nothing at all.

“Our approach revealed a ‘Goldilocks and The Three Bears’ phenomenon, in which T cells that had responded really well during the first infection then made either a big, medium or no response during the second infection,” said Associate Professor Haque.

“This previously unknown diversity in the immune response provides valuable insights into how children, who frequently experience multiple severe malaria infections within short time frames, may react during these periods.”

The study showed that CD4+ T cells responsible for guiding antibody production in the body remained focussed on their task despite the possible distractions of a new infection, while other CD4+ T cells thought to retain memory of the first infection, responded rapidly in a way that was almost identical to that first response.

Associate Professor Haque said these findings highlight the complexity and sophistication of the immune response to malaria.

“We think the immune system is intelligent enough to protect immune cells during re-infection, allowing them to continue instructing the body’s antibody factory, otherwise known as B cells, to make antibodies.”  

In a recently published study in Cell Reports, the same team of researchers detailed how spatial transcriptomics and computer science can be used to locate immune cells in tissues, and provide detailed insights into how cells might interact with each other.

“We also believe that spatial transcriptomics, or tissue genomics, not only offers hope for better understanding of malaria, but also has the potential to revolutionise how we approach the diagnosis and treatment of any disease that affects a human tissue, ultimately saving lives and improving health outcomes for children and adults worldwide,” he added.

Future research will continue to explore the detailed molecular pathways and cellular interactions that control CD4+ T cell function in malaria. This knowledge could pave the way for new interventions that boost the immune system's ability to combat this deadly disease.

Peer review: Lee HJ, Moreira ML, et al. CD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites. Nature Communications, (2024).   https://doi.org/10.1038/s41467-024-49879-6

Collaboration:  University of Melbourne, Broad Institute of MIT and Harvard University

Funding: National Health and Medical Research Council