During the course of a malaria infection, a wide array of immune effectors are activated. The first acute phase stimulates an inflammatory response with the release of cytotoxic compounds followed by acquired response and antibody production. Previous exposure to the pathogen confers a partial protection to a subsequent infection, a phenomenon coined ‘premunition’ by very early work on avian malaria [51]. Cellier Holzem et al. [52] infected immunologically naive domestic canaries with Plasmodium relictum. Thirty-four days after this primary

infection, when the birds had recovered their initial haematocrit and body mass values, surviving canaries were re-infected with the homologous strain. In agreement with the idea of premunition, re-exposed birds were better able to cope with the infection, keeping parasitaemia at lower levels and managing to maintain constant haematocrit

Palbociclib and body mass. Primary infected canaries produced more haptoglobin, a protein of the acute-phase response, compared with noninfected birds. However, haptoglobin did not differ between primary and secondary infected birds, suggesting that while inflammatory effectors are involved in the control of the initial acute phase of the infection, long-lasting partial immunity relies on memory effectors. Pioneering work conducted on CB-839 in vitro rodent malaria has stressed the importance of host immunity as a component of malaria virulence. Pro-inflammatory cytokines are important immune effectors involved in malaria resistance. Up-regulation of pro-inflammatory cytokines is often associated with a resistance phenotype

prone to immunopathology damage. On the contrary, up-regulation of anti-inflammatory cytokines confers a susceptible phenotype to microparasites and a protection towards immunopathology. Long et al. [53, 54] used phenotypic manipulations of both pro- and anti-inflammatory cytokines in mice infected oxyclozanide with Plasmodium chabaudi. They found that blockade of IL-10 (an anti-inflammatory cytokine) reduced parasitaemia but, nevertheless, exacerbated malaria virulence (i.e. mouse mortality) [53]. Similarly, blocking the TNF-α receptors induced an increase in parasite density while reducing disease severity [54]. Overall, there is strong evidence based on human and rodent studies that malaria virulence has an immune-based component [55, 56]. Building on this previous work, Bichet et al. [57] experimentally infected domestic canaries whose inducible nitric oxide synthase (iNOS) activity was inhibited by a drug (aminoguanidine). Inducible nitric oxide synthase catalyses the production of nitric oxide (NO), a nitrogen reactive species with cytostatic and cytotoxic effect on different Plasmodium species both in vitro and in vivo [58].