Host-mediated impairment of parasite maturation during blood-stagePlasmodiuminfection

Abstract

<p id="d981166e279">Adaptive immunity to <i>Plasmodium falciparum</i> takes years to develop in endemic regions, leaving young children vulnerable to high parasite burdens and severe malaria. Host innate immune responses clearly occur during infection and may control parasite numbers in nonimmune individuals, for example by accelerating parasite removal from circulation. However, evidence of whether and how this occurs in vivo remains sparse. We set out to measure host removal of parasites during acute blood-stage <i>Plasmodium</i> infection in mice. However, rather than being removed more rapidly, parasites unexpectedly persisted in circulation. Persistence resulted from host-dependent slowing of parasite maturation. Thus <i>Plasmodium</i> maturation within red blood cells does not occur at a constant rate in vivo and can be influenced by the host itself. </p><p class="first" id="d981166e291">Severe malaria and associated high parasite burdens occur more frequently in humans lacking robust adaptive immunity to <i>Plasmodium falciparum</i>. Nevertheless, the host may partly control blood-stage parasite numbers while adaptive immunity is gradually established. Parasite control has typically been attributed to enhanced removal of parasites by the host, although in vivo quantification of this phenomenon remains challenging. We used a unique in vivo approach to determine the fate of a single cohort of semisynchronous, <i>Plasmodium berghei</i> ANKA- or <i>Plasmodium yoelii</i> 17XNL-parasitized red blood cells (pRBCs) after transfusion into naive or acutely infected mice. As previously shown, acutely infected mice, with ongoing splenic and systemic inflammatory responses, controlled parasite population growth more effectively than naive controls. Surprisingly, however, this was not associated with accelerated removal of pRBCs from circulation. Instead, transfused pRBCs remained in circulation longer in acutely infected mice. Flow cytometric assessment and mathematical modeling of intraerythrocytic parasite development revealed an unexpected and substantial slowing of parasite maturation in acutely infected mice, extending the life cycle from 24 h to 40 h. Importantly, impaired parasite maturation was the major contributor to control of parasite growth in acutely infected mice. Moreover, by performing the same experiments in <i>rag1</i> ^{<i>−/−</i>} mice, which lack T and B cells and mount weak inflammatory responses, we revealed that impaired parasite maturation is largely dependent upon the host response to infection. Thus, impairment of parasite maturation represents a host-mediated, immune system-dependent mechanism for limiting parasite population growth during the early stages of an acute blood-stage <i>Plasmodium</i> infection. </p>