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

Benjamin M. Althouse,Tsukushi Kamiya,Nicole Mideo,Megan A Greischar,David S Schneider

doi:10.1371/journal.pcbi.1008211

Benjamin M. Althouse, Tsukushi Kamiya + Show 3 more

Open Access

https://doi.org/10.1371/journal.pcbi.1008211

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Abstract

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 impacts 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 acute Plasmodium 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 burst size, which is linked to the rate of host cells lost to malaria infection. General host vigour in the absence of infection was also correlated with host health during malaria infection. Our work demonstrates that the reaction norm approach provides a useful quantitative framework for examining the impact of a continuous external factor on within-host infection processes.

Highlights

IntroductionFor example, outcomes of infection with the same parasite, Plasmodium falciparum, range from sub-clinical to fatal [1]
The second response we considered was the induction of innate immunity targeting infected red blood cells (iRBCs) only, which is considered predominantly responsible for controlling the acute phase of malaria infection [43]
We found evidence for dose-dependence in key parameters of host responses underlying the dynamics of red blood cell (RBC) and iRBCs

Summary

Introduction

For example, outcomes of infection with the same parasite, Plasmodium falciparum, range from sub-clinical to fatal [1]. Understanding drivers of variation in infection outcomes is central to explaining why some hosts get sicker than others. Some host and parasite factors underlying this variation have well-understood mechanisms. The resistance mechanism of this single locus trait has been corroborated by four decades of research demonstrating that sickling enhances clearance of infected red blood cells (iRBCs) by host immune effectors like macrophages [2]. Unlike the sickle-cell trait, there are numerous sources of heterogeneity—including in the initial infection dose, nutrition, coinfection, and other genetic factors—for which quantitative impacts on outcomes have been observed, but causal mechanisms have remained elusive [3,4,5,6]. To establish a causal link between complex factors and infection outcomes, a key challenge is to quantify how a factor of interest mediates key host and parasite processes, such as host responses to infection and parasite growth [7]

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