A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration

Mejia, P., Treviño-Villarreal, J. H., Reynolds, J. S., De Niz, M., Thompson, A., Marti, M. and Mitchell, J. R. (2017) A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration. Malaria Journal, 16, 455. (doi: 10.1186/s12936-017-2092-5) (PMID:29121917) (PMCID:PMC5679345)

Abstract

Background: Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite oppor‑ tune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through efects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit transla‑ tional potential as an adjunctive therapy in CM. Results: The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of acti‑ vated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. Conclusions: Rapamycin exerts pleotropic efects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.

• Item Type: Articles
• Keywords: Cerebral malaria, endothelial activation, parasite sequestration, rapamycin.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Marti, Professor Matthias and De Niz, Dr Mariana
• Authors: Mejia, P., Treviño-Villarreal, J. H., Reynolds, J. S., De Niz, M., Thompson, A., Marti, M., and Mitchell, J. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Malaria Journal
• Publisher: BioMed Central
• ISSN: 1475-2875
• ISSN (Online): 1475-2875
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Malaria Journal 16: 455
• Publisher Policy: Reproduced under a Creative Commons License