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

Abstract

BackgroundMaladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM.ResultsThe 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 activated 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.ConclusionsRapamycin exerts pleotropic effects 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.

Excretion of Ascaris lumbricoides following reduced‐intensity allogeneic hematopoietic stem cell transplantation and consecutive treatment with mebendazole

“…Fludarabine, a purine analogue, and treosulfan, an alkylating agent, are assumed to interfere with helminths' cell cycle and with human bone marrow cells . The immunosuppressive agents sirolimus and MMF also might have had a strong effect on the worm's cell cycle …”

“…15 The immunosuppressive agents sirolimus and MMF also might have had a strong effect on the worm's cell cycle. [16][17][18][19][20]…”

The host mTOR pathway and parasitic diseases pathogenesis

“…In 2017, a similar study revealed the protective properties of rapamycin in experimental CM. This study indicated that rapamycin induced the reduction of neuropathology and death via the regulation of host responses to CM infection (Mejia et al 2017 ). After the treatment with rapamycin, the parasite cytoadherence was inhibited through the downregulation of CD36 in peripheral organs such as white adipose tissue.…”

“…The administration of rapamycin in infected mice with CM blocked the breakdown of the blood–brain barrier, reduced the brain hemorrhage, and increased the survival rate of infected mice demonstrating the immunoregulatory functions of mTOR as well as the therapeutic properties of rapamycin in CM. In addition, such a treatment diminished the influx of T cells (CD4 and CD8) into the brain and reduced the accumulation of infected erythrocytes in the brain of infected mice with CM (Gordon et al 2015 ; Mejia et al 2017 ). Moreover, leukocyte trafficking to the brain and leukocyte proliferation in the brain was blocked in infected mice treated by rapamycin (Gordon et al 2015 ).…”

Blood–Brain Barrier in Cerebral Malaria: Pathogenesis and Therapeutic Intervention

“…Sequestration of iRBCs can also be prevented by the use of drugs targeting cytoadherence of iRBCs. Rapamycin prevents the cytoadherence of iRBCs via reduction of ICAM-1 and VCAM-1 expression in ECM [29]. Moreover, ethanolic extracts of the fungus Trichoderma stromaticum decrease inflammation and ameliorate ECM by reducing cerebral expression of ICAM-1 and VCAM-1, thereby preserving BBB integrity [30].…”