Cross-reactive immune responses as primary drivers of malaria chronicity

Eili Y. Klein, Andrea L. Graham, Manuel Llinás, Simon Levin

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)140-151
Number of pages12
JournalInfection and Immunity
Volume82
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Malaria
Infection
Parasites
Antigenic Variation
Immune System
Antigens
Falciparum Malaria
Erythrocyte Membrane
Plasmodium falciparum
Membrane Proteins
Erythrocytes

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Klein, Eili Y. ; Graham, Andrea L. ; Llinás, Manuel ; Levin, Simon. / Cross-reactive immune responses as primary drivers of malaria chronicity. In: Infection and Immunity. 2014 ; Vol. 82, No. 1. pp. 140-151.
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Cross-reactive immune responses as primary drivers of malaria chronicity. / Klein, Eili Y.; Graham, Andrea L.; Llinás, Manuel; Levin, Simon.

In: Infection and Immunity, Vol. 82, No. 1, 01.01.2014, p. 140-151.

Research output: Contribution to journalArticle

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