Proposed model by which children remain asymptomatic and control parasitemia upon <i>P. falciparum</i> re-exposure.

<p>In children without prior or recent malaria exposure, <i>P. falciparum</i> infection induces a robust pro-inflammatory cytokine and chemokine response (e.g. IL-1β, IL-6, IL-8) whereas effector mechanisms that mediate parasite clearance (phagocytosis, phagolysosome activation, antigen presentation, T cell co-stimulation and IFN-<b>γ</b> production by CD4⁺ T cells) are not readily inducible, leaving children susceptible to fever and other systemic symptoms of malaria as well as poorly controlled parasite replication. In contrast, febrile malaria induces an exposure-dependent regulatory state (shown here) whereby re-exposure to <i>P. falciparum</i> results in reduced production of pro-inflammatory cytokines and chemokines and enhanced expression of regulatory cytokines (e.g. IL-10 production by CD4⁺ T cells) and pathways involved in phagocytosis-mediated clearance of infected red blood cells and activation of adaptive immunity, thus enabling children to remain asymptomatic and control parasite replication in the face of ongoing <i>P. falciparum</i> exposure. In addition, <i>P. falciparum</i>-specific IgG levels are low in children who have not been recently exposed to malaria, but transiently increase in response to <i>P. falciparum</i> infection <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004079#ppat.1004079-Weiss1" target="_blank">[44]</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004079#ppat.1004079-Crompton2" target="_blank">[45]</a>, further enhancing exposure-dependent parasite clearance through opsonization and phagocytosis of infected erythrocytes. Arrows indicate the direction of expression observed in this study of molecules at the mRNA and/or protein levels induced by <i>P. falciparum</i> re-exposure after febrile malaria relative to responses induced by <i>P. falciparum</i> exposure at the healthy baseline. Molecules are color-coded by biological function.