Uncovering drivers of dose-dependence and individual variation in malaria infection outcomes

by Tsukushi Kamiya, Megan A. Greischar, David S. Schneider, Nicole Mideo To understand why some hosts get sicker than others from the same type of infection, it is essential to explain how key processes, such as host responses to infection and parasite growth, are influenced by various biotic and abiotic factors. In many disease systems, the initial infection dose impa cts host morbidity and mortality. To explore drivers of dose-dependence and individual variation in infection outcomes, we devised a mathematical model of malaria infection that allowed host and parasite traits to be linear functions (reaction norms) of the initial dose. We fitted the model, using a hierarchical Bayesian approach, to experimental time-series data of acutePlasmodium chabaudi infection across doses spanning seven orders of magnitude. We found evidence for both dose-dependent facilitation and debilitation of host responses. Most importantly, increasing dose reduced the strength of activation of indiscriminate host clearance of red blood cells while increasing the half-life of that response, leading to the maximal response at an intermediate dose. We also explored the causes of diverse infection outcomes across replicate mice receiving the same dose. Besides random noise in the injected dose, we found variation in peak parasite load was due to unobserved individual variation in host responses to clear infected cells. Individual variation in anaemia was likely driven by random variation in parasite...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research

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Source: Advances in Hematology - Category: Hematology Tags: Adv Hematol Source Type: research
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Source: The American Journal of Tropical Medicine and Hygiene - Category: Tropical Medicine Authors: Tags: Am J Trop Med Hyg Source Type: research
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Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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