Immune regulation of host energy metabolism and periodicity of malaria parasites.

Abstract

The synchronization of Plasmodium parasites as they replicate within red blood cells of their vertebrate host remains largely unexplored. Understanding this synchronization could reveal how parasites optimize their lifecycle to maximize transmission, evade the immune response and maximize energy acquisition. Rhythmic replication fulfils some criteria of an endogenous oscillator with time of day cues potentially provided by temperature, oxygen levels, hormones and/or nutrient availability. Recent research on a rodent malaria model has highlighted that rhythms associated with the host's feeding/fasting cycle are a crucial factor influencing the synchronization of the erythrocytic stages of Plasmodium to the host's circadian cycle. Innate immune responses are also rhythmic and can regulate host metabolism, suggesting that the innate immune response triggered by Plasmodium contributes to its rhythmic replication. Here, we outline how the interplay between immune responses and metabolism could influence the timing and synchronization of Plasmodium's replication rhythm, focusing on the roles of the cytokine tumour necrosis factor, mitochondrial function and metabolites generated by the tricarboxylic acid cycle in highly activated monocytes. These processes are pivotal in controlling parasitemia and determining disease outcome, suggesting that a better understanding of energy metabolism on rhythmic host-parasite interactions may provide new insights for therapeutic interventions against malaria.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.