Cross-reactive immune responses as primary drivers of malaria chronicity.

TitleCross-reactive immune responses as primary drivers of malaria chronicity.
Publication TypeJournal Article
Year of Publication2014
AuthorsKlein EY, Graham AL, LlinĂ¡s M, Levin S
JournalInfect Immun
Date Published2014 Jan
KeywordsAntigenic Variation, Antigens, Protozoan, Chronic Disease, Cross Reactions, Host-Parasite Interactions, Humans, Immune Evasion, Malaria, Falciparum, Models, Biological, Plasmodium falciparum, Protozoan Proteins

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.

Alternate JournalInfect. Immun.
PubMed ID24126530
PubMed Central IDPMC3911831
Grant List5U54GM088491 / GM / NIGMS NIH HHS / United States
DP1OD003874 / OD / NIH HHS / United States
P50 GM071508 / GM / NIGMS NIH HHS / United States
P50 GM071508 / GM / NIGMS NIH HHS / United States
U54 GM088491 / GM / NIGMS NIH HHS / United States
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