Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

Abstract

The within-host dynamics of an infection with the malaria parasite Plasmodium falciparum are the result of a complex interplay between the host immune system and parasite. Continual variation of the P. falciparum erythrocyte membrane protein (PfEMP1) antigens displayed on the surface of infected red blood cells enables the parasite to evade the immune system and prolong infection. Despite the importance of antigenic variation in generating the dynamics of infection, our understanding of the mechanisms by which antigenic variation generates long-term chronic infections is still limited. We developed a model to examine the role of cross-reactivity in generating infection dynamics that are comparable to those of experimental infections. The hybrid computational model we developed is attuned to the biology of malaria by mixing discrete replication events, which mimics the synchrony of parasite replication and invasion, with continuous interaction with the immune system. Using simulations, we evaluated the dynamics of a single malaria infection over time. We then examined three major mechanisms by which the dynamics of a malaria infection can be structured: cross-reactivity of the immune response to PfEMP1, differences in parasite clearance rates, and heterogeneity in the rate at which antigens switch. The results of our simulations demonstrate that cross-reactive immune responses play a primary role in generating the dynamics observed in experimentally untreated infections and in lengthening the period of infection. Importantly, we also find that it is the primary response to the initially expressed PfEMP1, or small subset thereof, that structures the cascading cross-immune dynamics and allows for elongation of the infection.

Predicting optimal transmission investment in malaria parasites

“…Model simulations of human infections suggest that the time required for immune clearance is an extremely complex function of the parasites' proliferation rates coupled with their antigenic repertoires, although parasites that replicate rapidly initially should be better able to modulate immune defenses and prolong infection (Klein et al. ). Despite these unknowns, we find that infection length is unlikely to alter selection against early transmission investment or to eliminate the benefit of restraining reproduction when parasite populations are in decline (Fig.…”

“…Analysis of experimental rodent infections suggests that rapid parasite proliferation lessens the impact of early immunity and hastens escalation of the adaptive immune response, but neither of these host responses terminate infection, at least over the 50 days examined (Metcalf et al 2011). Model simulations of human infections suggest that the time required for immune clearance is an extremely complex function of the parasites' proliferation rates coupled with their antigenic repertoires, although parasites that replicate rapidly initially should be better able to modulate immune defenses and prolong infection (Klein et al 2014). Despite these unknowns, we find that infection length is unlikely to alter selection against early transmission investment or to eliminate the benefit of restraining reproduction when parasite populations are in decline (Fig.…”

“…Though gametocytes trigger minimal innate immune response (Riley and Stewart 2013), their circulation times may be limited by antibody responses (reviewed in Bousema and Drakeley 2011). The adaptive immune response is thought to be inherently stochastic, dependent on which parasite antigens are predominantly expressed to the immune system at the beginning of infection (Klein et al 2014). Further work is needed to determine if hosts rapidly diverge in their antibody responses in a way that impacts gametocyte longevity, and whether parasites can sense and respond to those changes; if so, we would expect parasites to benefit from employing divergent transmission investment strategies across otherwise similar hosts.…”

Partitioning the influence of ecology across scales on parasite evolution

“…Mechanistic models likewise suggest that rapid proliferation early in infection can delay recovery (Klein et al. ). Therefore, the bulk of current evidence is consistent with rapid proliferation slowing recovery rates; consequently, increased transmission investment—by reducing the realized rate of parasite proliferation—would be expected to hasten recovery (Fig.…”

“…; Klein et al. ). By modulating parasite abundance and transmission potential over the course of infection, switching patterns will be subject to selection from larger scale epidemiology.…”