Understanding and Predicting Strain-Specific Patterns of Pathogenesis in the Rodent Malaria Plasmodium chabaudi

Despite considerable success elucidating important immunological and resource-based mechanisms that control the dynamics of infection in some diseases, little is known about how differences in these mechanisms result in strain differences in patterns of pathogenesis. Using a combination of data and theory, we disentangle the role of ecological factors (e.g., resource abundance) in the dynamics of pathogenesis for the malaria species Plasmodium chabaudi in CD4(+) T cell-depleted mice. We build a series of nested models to systematically test a number of potential regulatory mechanisms and determine the "best" model using statistical techniques. The best-fit model is further tested using an independent data set from mixed-clone competition experiments. We find that parasites preferentially invade older red blood cells even when they are more fecund in younger reticulocytes and that inoculum size has a strong effect on burst size in reticulocytes. Importantly, the results suggest that strain-specific differences in virulence arise from differences in red blood cell age-specific invasion rates and burst sizes, since these are lower for the less virulent strain, as well as from differences in levels of erythopoesis induced by each strain. Our analyses highlight the importance of model selection and validation for revealing new biological insights.