Epigenetic regulation of innate immune genes and enhanced interleukin-10 expression underlie chronic subclinical Plasmodium chabaudi infection

de Souza Silva, L.; Nguyen, Y. A. H.; Monks, B. G.; Forconi, C. S.; Crabtree, J. N.; Rodriguez, T.; Tamburro, N. D. P.; Sontheimer, E. J.; Horvath, G. L.; Abdullah, Z.; Latz, E.; Caffrey, D. R.; Kurt-Jones, E.; Gazzinelli, R. T.; Fitzgerald, K. A.; Golenbock, D. T.

doi:10.1101/2023.02.23.529826

bioRxiv · 10.1101/2023.02.23.529826

Epigenetic regulation of innate immune genes and enhanced interleukin-10 expression underlie chronic subclinical Plasmodium chabaudi infection

de Souza Silva, L.·Nguyen, Y. A. H.·Monks, B. G.·Forconi, C. S.·Crabtree, J. N.·Rodriguez, T.·Tamburro, N. D. P.·Sontheimer, E. J.·Horvath, G. L.·Abdullah, Z.·Latz, E.·Caffrey, D. R.·Kurt-Jones, E.·Gazzinelli, R. T.·Fitzgerald, K. A.·Golenbock, D. T.

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Abstract

Subclinical (asymptomatic) parasitemia is very common amongst Plasmodium-infected individuals. The immunological mechanisms underlying subclinical parasitemia remain elusive. We investigated the immune regulatory mechanisms behind chronic asymptomatic Plasmodium infection using mice lacking humoral immunity ({micro}MT-/- mice). {micro}MT-/- mice became chronically infected, despite lacking outward signs of disease, and exhibited increased macrophage numbers, decreased dendritic and CD4 cells, massive hemozoin accumulation in the spleen and bone marrow, and inadequate hematopoiesis. These changes were accompanied by high circulating levels of interleukin-10 (IL-10), enhanced chromatin accessibility of the STAT3 promoter, and enhanced STAT3 binding to the IL-10 promoter in macrophages. Inhibition of IL-10 signaling, despite promoting parasite clearance, resulted in a proinflammatory response, weight loss, and mortality. These results suggest that epigenetic changes induced by chronic P. chabaudi infection lead to high levels of circulating IL-10, protecting chronically infected mice against an excessive inflammatory response to high levels of blood-stage parasites. Author summaryMalaria is a life-threatening disease with a range of symptoms, and it is induced in humans by infections with different species of Plasmodium. Highly prevalent in endemic regions, asymptomatic Plasmodium infections are related to long-term exposure to the parasite due to multiple infections and have been demonstrated in human and mouse studies to be associated with elevated levels of IL-10. However, how IL-10 levels remain elevated in the circulation in individuals over the long term has not been determined. We used a mouse model of chronic asymptomatic Plasmodium infection to investigate the mechanisms by which IL-10 levels are elevated during chronic asymptomatic infection. Our results show that epigenetic changes in immune genes of myeloid origin could be responsible for the elevated levels of IL-10, and that IL-10 signaling protected chronically infected mice from a severe inflammatory response induced by the infection.

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de Souza Silva, L., Nguyen, Y. A. H., Monks, B. G., Forconi, C. S., Crabtree, J. N., Rodriguez, T., Tamburro, N. D. P., Sontheimer, E. J., Horvath, G. L., Abdullah, Z., Latz, E., Caffrey, D. R., Kurt-Jones, E., Gazzinelli, R. T., Fitzgerald, K. A., Golenbock, D. T.. 2023-02-24. Epigenetic regulation of innate immune genes and enhanced interleukin-10 expression underlie chronic subclinical Plasmodium chabaudi infection. https://doi.org/10.1101/2023.02.23.529826

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