On the control of acute rodent malaria infections by innate immunity

Abstract

Does specific immunity, innate immunity or resource (red blood cell) limitation control the first peak of the blood-stage parasite in acute rodent malaria infections? Since mice deficient in specific immunity exhibit similar initial dynamics as wild-type mice it is generally viewed that the initial control of parasite is due to either limitation of resources (RBC) or innate immune responses. There are conflicting views on the roles of these two mechanisms as there is experimental evidence supporting both these hypotheses. While mathematical models based on RBC limitation are capable of describing the dynamics of primary infections, it was not clear whether a model incorporating the key features of innate immunity would be able to do the same. We examine the conditions under which a model incorporating parasite and innate immunity can describe data from acute Plasmodium chabaudi infections in mice. We find that innate immune response must decay slowly if the parasite density is to fall rather than equilibrate. Further, we show that within this framework the differences in the dynamics of two parasite strains are best ascribed to differences in susceptibility to innate immunity, rather than differences in the strains' growth rates or their propensity to elicit innate immunity. We suggest that further work is required to determine if innate immunity or resource limitation control acute malaria infections in mice.

Figure 1. Schematic of model.

In our model the density of the parasite, , depends on two factors – its own replication (at rate ) and its clearance by activated innate immune cells at rate . The total number of innate immune cells equals and they can be either in a resting or activated state. Since is the number of activated cells, the number of resting cells equals . Resting innate immune cells are activated at rate , and revert back to the inactive state at exponential rate .

Figure 2. Experimental data and models for the dynamics of strains AS (red dashed lines) and AJ (blue solid lines).

We use the model described in the text to investigate whether the dynamics of AS and AJ could be explained by (I) AJ having a higher growth rate than AS; (II) AJ inducing innate immunity more slowly than AS; or (III) AJ being less susceptible to killing by innate immunity than AS. Host Parameters: (that is, no innate immunity is activated at infection), day and . Strain parameters are estimated using the single infection data from days 2–10 only (unshaded area). Strain parameters, I: cells, day, day, dayscells, day. II: cells, day, dayscells, dayscells, . III: cells, day, dayscells, day, day. The left-hand column shows the mean parasite counts over time from experimental data for single infections (panel a; n = 11 (AJ) and n = 14 (AS)) and co-infections (panels e, i, m; n = 4, 4 and 5 respectively).