The contribution of host cell-directed vs. parasite-directed immunity to the disease and dynamics of malaria infections

Abstract

Hosts defend themselves against pathogens by mounting an immune response. Fully understanding the immune response as a driver of host disease and pathogen evolution requires a quantitative account of its impact on parasite population dynamics. Here, we use a data-driven modeling approach to quantify the birth and death processes underlying the dynamics of infections of the rodent malaria parasite, Plasmodium chabaudi, and the red blood cells (RBCs) it targets. We decompose the immune response into 3 components, each with a distinct effect on parasite and RBC vital rates, and quantify the relative contribution of each component to host disease and parasite density. Our analysis suggests that these components are deployed in a coordinated fashion to realize distinct resource-directed defense strategies that complement the killing of parasitized cells. Early in the infection, the host deploys a strategy reminiscent of siege and scorched-earth tactics, in which it both destroys RBCs and restricts their supply. Late in the infection, a "juvenilization" strategy, in which turnover of RBCs is accelerated, allows the host to recover from anemia while holding parasite proliferation at bay. By quantifying the impact of immunity on both parasite fitness and host disease, we reveal that phenomena often interpreted as immunopathology may in fact be beneficial to the host. Finally, we show that, across mice, the components of the host response are consistently related to each other, even when infections take qualitatively different trajectories. This suggests the existence of simple rules that govern the immune system's deployment.

Keywords: Plasmodium chabaudi; immune response; immunopathology; red blood cells; top-down vs. bottom-up control.

Fig. 1.

Decomposing the host immune response. (A) The daily cycle of malaria parasites in the blood stage of infection. Each day, parasite offspring (merozoites) burst from RBCs and then attempt to invade new RBCs, wherein they mature and reproduce. In our model, the host immune response modulates infection by killing RBCs and adjusting their supply. Samples were taken from experimentally infected mice each morning, before parasites had reproduced, and were processed to produce time-series data on infection dynamics (see B). (B) Time series of reticulocyte (i.e., immature RBC), parasite, and total (mature + immature) RBC densities. (C) Eq. 1 shows how these 3 data streams can be transformed into 3 synthetic variables (components of the immune response), which describe the impacts of the immune response on parasite proliferation and host health (anemia). In particular, RBCs can be killed by a response targeted at parasitized cells or by a response that kills RBCs irrespective of their infection status. Moreover, the host can modulate the supply of reticulocytes. The model works by projecting the density of RBCs and parasites at the next time step (t + 1) in the absence of any killing, given the abundance of RBCs and parasites at time t and the supply of RBCs at time t + 1. The deficit between these projections and the data is then partitioned among the indiscriminate and targeted killing components. (D) This procedure yields, for each infected mouse, time series of the 3 immune-response components. By comparing these trajectories across mice, we identify robust patterns which can be interpreted in terms of host defense strategy.

Fig. 2.

The model accurately captures the data and yields the dynamics of 3 qualitatively distinct host responses. (A–C) Measured (black) and fitted (orange) densities of parasitized RBCs (A), reticulocytes (B), and total RBCs (C) in 3 mice which were (left to right) fed a 0.005% concentration, 0.0005% concentration, and a 0% solution of pABA, a nutrient that stimulates parasite growth rate. Data and fitted model trajectories for all mice are shown in SI Appendix, Figs. S1 and S2. (D) Estimated trajectories of 3 distinct host responses that target parasitized cells only (“targeted killing”; purple) and RBCs irrespective of their infection status (indiscriminate killing; blue) and that resupply reticulocytes (pink). Note that these responses are of the same order of magnitude as the RBCs. Plotted are the mean (solid line) and 90% confidence interval (ribbon) on the smoothed estimate of the model trajectories.

Fig. 3.

Contribution of the different components of the host response to parasite fitness and host disease. (A) Contribution of the host to the (suppression of) parasite reproduction in 3 different mice (left to right), each of which was fed a different concentration of a nutrient that stimulates parasite growth. The dashed line indicates the maximum number of offspring that could be produced per parasitized cell in conditions of unlimited RBC availability; the fill area indicates the estimated number of offspring that successfully emerged (pinks), were destroyed by each of the killing responses (blues), or were not produced due to the limited availability of RBCs (brown). The black horizontal line indicates 1 offspring/parasite: When the blue area descends below this line, the parasite population is decreasing in size. (B) The uncolored part of the bar indicates the number of the previous day’s losses that were compensated for by the present day’s supply of reticulocytes (turnover); the colored section indicates the extent to which the present day’s supply of reticulocytes exceeded yesterday’s losses (“surplus”; black) or failed to compensate for them (“deficit”; red). (C) The relative contribution of parasites and each of the host responses to the fate of RBCs through time. Note that parasites can contribute to RBC destruction directly, by emergence, or indirectly via the targeted killing response. The white vertical line in A and C indicates the time of peak parasite density. Shown are the decompositions for the same 3 mice used in all other figures. Equivalent plots for the 9 other mice analyzed can be found in SI Appendix, Fig. S3.

Fig. 4.

The components of the immune response are similarly deployed, even among mice displaying different infection dynamics. (A–C) The relationships between the 3 components of the host response. The large, black-outlined dot indicates the starting point of the infection. Each subsequent day is marked with a dot, with large dots indicating days 5, 10, 15, and 20. Landmarks a and b identify transitions between regimens of deployment of the components that occur, as summarized in D. (NB: The timing of these landmarks is consistent across all mice in the analysis, with the exception of 2 mice that received fewer parasites than intended; SI Appendix, Figs. S1 and S4.) (D) The dashed red line indicates that parasite density increases in some, but not all, mice during the period indicated. Densities of parasites and RBCs are in units per microliter of blood. These trajectories are from the same 3 mice whose infections are displayed in Figs. 2 and 3, each of which received a different concentration of pABA, a nutrient that alters parasite growth rate.