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Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites.

Santhanam, Jayanthi; Råberg, Lars LU ; Read, Andrew F and Savill, Nicholas Jon (2014) In PLoS Computational Biology 10(1).
Abstract
Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and... (More)
Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter [Formula: see text], the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, [Formula: see text] was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery. (Less)
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organization
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publication status
published
subject
in
PLoS Computational Biology
volume
10
issue
1
publisher
Public Library of Science
external identifiers
  • pmid:24465193
  • wos:000337948500017
  • scopus:84896696589
ISSN
1553-7358
DOI
10.1371/journal.pcbi.1003416
language
English
LU publication?
yes
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94dd6e66-e57c-4996-94dc-4ecde63d0f06 (old id 4290633)
date added to LUP
2014-02-28 11:53:21
date last changed
2017-08-13 03:14:51
@article{94dd6e66-e57c-4996-94dc-4ecde63d0f06,
  abstract     = {Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter [Formula: see text], the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, [Formula: see text] was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery.},
  articleno    = {e1003416},
  author       = {Santhanam, Jayanthi and Råberg, Lars and Read, Andrew F and Savill, Nicholas Jon},
  issn         = {1553-7358},
  language     = {eng},
  number       = {1},
  publisher    = {Public Library of Science},
  series       = {PLoS Computational Biology},
  title        = {Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites.},
  url          = {http://dx.doi.org/10.1371/journal.pcbi.1003416},
  volume       = {10},
  year         = {2014},
}