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The dynamics of naturally acquired immunity to Plasmodium falciparum infection.

Pinkevych M, Petravic J, Chelimo K, Kazura JW, Moormann AM, Davenport MP - PLoS Comput. Biol. (2012)

Bottom Line: Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity.We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites.We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains.

View Article: PubMed Central - PubMed

Affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.

ABSTRACT
Severe malaria occurs predominantly in young children and immunity to clinical disease is associated with cumulative exposure in holoendemic settings. The relative contribution of immunity against various stages of the parasite life cycle that results in controlling infection and limiting disease is not well understood. Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity. We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites. We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains. Analysis and modelling of malaria infection dynamics and naturally acquired immunity with age provides important insights into what mechanisms of immune control may be harnessed by malaria vaccine strategists.

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Related in: MedlinePlus

Reinfection and parasitaemia with blood stage immunity.The dynamics of reinfection (A) and the mean parasitaemia (B) are shown for the stochastic simulation of acquired blood stage immunity. Panel A. Mean (calculated every 7 days) of 5 simulations of the reinfection curves of individuals with general and strain specific immunity with parameters listed in Table S2.1. in [Text S2]. Blue triangle and blue line- 0–4 y.o., green diamond and green line - 5–9 y.o., orange square and orange line - 10–14 y.o., red circle and red line - 15–30 y.o. Panel B. Average concentration of parasites in blood in the field study data (left 4 bars) and in the simulated reinfection data presented in the panel A.
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pcbi-1002729-g006: Reinfection and parasitaemia with blood stage immunity.The dynamics of reinfection (A) and the mean parasitaemia (B) are shown for the stochastic simulation of acquired blood stage immunity. Panel A. Mean (calculated every 7 days) of 5 simulations of the reinfection curves of individuals with general and strain specific immunity with parameters listed in Table S2.1. in [Text S2]. Blue triangle and blue line- 0–4 y.o., green diamond and green line - 5–9 y.o., orange square and orange line - 10–14 y.o., red circle and red line - 15–30 y.o. Panel B. Average concentration of parasites in blood in the field study data (left 4 bars) and in the simulated reinfection data presented in the panel A.

Mentions: Fig. 4 shows the dynamics of parasite infection and acquisition of strain specific and general immunity by an individual, starting from birth to one year [left panel] and five to six years [right panel]. The top panels show the dynamics of parasite infection, as different parasite strains (indicated by different colours) initiate blood stage infection, grow, and then induce strain-specific immunity, leading to their clearance. Given the long half-life of strain-specific immunity and the absence of within-host parasite antigen variation in our model, each new parasitemia peak represents infection with a new strain. In addition to inducing strain-specific immunity (bottom panels, coloured), these infections also induce general immunity (solid black line), which accumulates over time. By simulating the life history of a small population of individuals (n = 50), we can then apply the concept of ‘treatment-time-to-infection’ trials to the simulated individuals. That is, by removing all blood stage parasites of individuals in different age groups and observing the time until parasite levels reach our detection threshold, we can simulate (re)-infection (Fig. 5 and 6). Fig. 5 shows the dynamics of parasitaemia during (re)-infection from the field study data (top) and the simulation (bottom), for four subjects from each of the different age groups. Remarkably, the simulation captures a number of the factors observed in our observational study; firstly, the natural infection curves show increasing delay with age and an increasing proportion of individuals remaining uninfected. Secondly, the observed reduction in parasite levels in blood with age is also captured in the model, indicating that the decreased PMR required to produce the reinfection curves is consistent with the decreased PMR required to produce the observed reduction in parasitaemia with age. (as higher immunity means parasites are controlled at a lower parasitaemia) (Fig. 5). Fig. 6A shows the infection curves for the whole simulated population, and Fig. 6B compares the mean parasitaemia for the field study data and simulation for different ages. Importantly, the major factor that can account for both delayed infection and lower parasitaemia in adults is simply a reduced average growth rate of parasites with age and naturally acquired immunity.


The dynamics of naturally acquired immunity to Plasmodium falciparum infection.

Pinkevych M, Petravic J, Chelimo K, Kazura JW, Moormann AM, Davenport MP - PLoS Comput. Biol. (2012)

Reinfection and parasitaemia with blood stage immunity.The dynamics of reinfection (A) and the mean parasitaemia (B) are shown for the stochastic simulation of acquired blood stage immunity. Panel A. Mean (calculated every 7 days) of 5 simulations of the reinfection curves of individuals with general and strain specific immunity with parameters listed in Table S2.1. in [Text S2]. Blue triangle and blue line- 0–4 y.o., green diamond and green line - 5–9 y.o., orange square and orange line - 10–14 y.o., red circle and red line - 15–30 y.o. Panel B. Average concentration of parasites in blood in the field study data (left 4 bars) and in the simulated reinfection data presented in the panel A.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3475668&req=5

pcbi-1002729-g006: Reinfection and parasitaemia with blood stage immunity.The dynamics of reinfection (A) and the mean parasitaemia (B) are shown for the stochastic simulation of acquired blood stage immunity. Panel A. Mean (calculated every 7 days) of 5 simulations of the reinfection curves of individuals with general and strain specific immunity with parameters listed in Table S2.1. in [Text S2]. Blue triangle and blue line- 0–4 y.o., green diamond and green line - 5–9 y.o., orange square and orange line - 10–14 y.o., red circle and red line - 15–30 y.o. Panel B. Average concentration of parasites in blood in the field study data (left 4 bars) and in the simulated reinfection data presented in the panel A.
Mentions: Fig. 4 shows the dynamics of parasite infection and acquisition of strain specific and general immunity by an individual, starting from birth to one year [left panel] and five to six years [right panel]. The top panels show the dynamics of parasite infection, as different parasite strains (indicated by different colours) initiate blood stage infection, grow, and then induce strain-specific immunity, leading to their clearance. Given the long half-life of strain-specific immunity and the absence of within-host parasite antigen variation in our model, each new parasitemia peak represents infection with a new strain. In addition to inducing strain-specific immunity (bottom panels, coloured), these infections also induce general immunity (solid black line), which accumulates over time. By simulating the life history of a small population of individuals (n = 50), we can then apply the concept of ‘treatment-time-to-infection’ trials to the simulated individuals. That is, by removing all blood stage parasites of individuals in different age groups and observing the time until parasite levels reach our detection threshold, we can simulate (re)-infection (Fig. 5 and 6). Fig. 5 shows the dynamics of parasitaemia during (re)-infection from the field study data (top) and the simulation (bottom), for four subjects from each of the different age groups. Remarkably, the simulation captures a number of the factors observed in our observational study; firstly, the natural infection curves show increasing delay with age and an increasing proportion of individuals remaining uninfected. Secondly, the observed reduction in parasite levels in blood with age is also captured in the model, indicating that the decreased PMR required to produce the reinfection curves is consistent with the decreased PMR required to produce the observed reduction in parasitaemia with age. (as higher immunity means parasites are controlled at a lower parasitaemia) (Fig. 5). Fig. 6A shows the infection curves for the whole simulated population, and Fig. 6B compares the mean parasitaemia for the field study data and simulation for different ages. Importantly, the major factor that can account for both delayed infection and lower parasitaemia in adults is simply a reduced average growth rate of parasites with age and naturally acquired immunity.

Bottom Line: Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity.We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites.We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains.

View Article: PubMed Central - PubMed

Affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.

ABSTRACT
Severe malaria occurs predominantly in young children and immunity to clinical disease is associated with cumulative exposure in holoendemic settings. The relative contribution of immunity against various stages of the parasite life cycle that results in controlling infection and limiting disease is not well understood. Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity. We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites. We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains. Analysis and modelling of malaria infection dynamics and naturally acquired immunity with age provides important insights into what mechanisms of immune control may be harnessed by malaria vaccine strategists.

Show MeSH
Related in: MedlinePlus