Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria
Department of Medicine, Division of Infectious Diseases and Immunology
Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease
Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.
DOI of Published Version
Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3689-94. doi:10.1073/pnas.1015406108. Epub 2011 Feb 8. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng W, Ataide MA, DeOliveira RB, Golenbock DT, Gazzinelli RT. (2011). Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Infectious Diseases and Immunology Publications. https://doi.org/10.1073/pnas.1015406108. Retrieved from https://escholarship.umassmed.edu/infdis_pp/380