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.

Partitioning Regulatory Mechanisms of Within-Host Malaria Dynamics Using the Effective Propagation Number

“…Previous work on malaria has fitted more mechanistically detailed dynamic models to time-series data on uninfected and infected cells (3, 4, 11-14, 26, 41). Our simpler statistical method confirms conclusions from this work (e.g., roles for age-structure of RBCs (12, 13) and clearance of uninfected RBCs (11)) but also identifies dynamical features not previously detected (e.g., dose-dependence in the impact of innate immunity and complex time-dependence in the efficacy of adaptive immunity).…”

“…Here we analyse experimental work on CD4+ T-cell depleted mice (22), intact mice infected at a range of starting parasite densities (23), and mice treated with a neutralizing antibody that acts to up-regulate immunity (24), all infected with the AS clone of P. chabaudi (see Figs S2-S4 and (25) for details). Framing our analysis in ecological terms (4, 14) we contrast bottom-up processes (analogous to resource availability for free-living organisms) with top-down mechanisms (analogous to control by natural enemies). There are two widely recognized bottom-up controls in malaria dynamics (3, 4, 11-13, 26-28): the availability of susceptible cells and age-dependent variation in susceptibility of these cells.…”

Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections

“…Our model of the innate immune response is similar to that in ref. 38. Activated effector cells are recruited into the site of the infection at a rate proportional to the density of cells in an inactive reservoir and a rate parameter η per hour.…”

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

“…Instead, the competition between coinfecting malaria parasites probably arises from competition for resources. Most likely, this competition is for access to red blood cells (44,(46)(47)(48)(49)(50)(51)(52)(53), although other resources, such as glucose, may also be involved (40). Immune-mediated apparent competition, wherein the immune response provoked by one strain suppresses the population densities of a coinfecting strain (11), likely also plays a major role (41,54).…”