Preferential Invasion by Plasmodium Merozoites and the Self-Regulation of Parasite Burden

Citation: Kerlin DH, Gatton ML ( Preferential Invasion by Plasmodium Merozoites and the Self-Regulation of Parasite Burden Douglas H. Kerlin 0 Michelle L. Gatton 0 Steffen Borrmann, Kenya Medical Research Institute - Wellcome Trust Research Programme, Kenya 0 Malaria Drug Resistance and Chemotherapy Laboratory, Queensland Institute of Medical Research , Brisbane, Queensland , Australia The preferential invasion of particular red blood cell (RBC) age classes may offer a mechanism by which certain species of Plasmodia regulate their population growth. Asexual reproduction of the parasite within RBCs exponentially increases the number of circulating parasites; limiting this explosion in parasite density may be key to providing sufficient time for the parasite to reproduce, and for the host to develop a specific immune response. It is critical that the role of preferential invasion in infection is properly understood to model the within-host dynamics of different Plasmodia species. We develop a simulation model to show that limiting the range of RBC age classes available for invasion is a credible mechanism for restricting parasite density, one which is equally as important as the maximum parasite replication rate and the duration of the erythrocytic cycle. Different species of Plasmodia that regularly infect humans exhibit different preferences for RBC invasion, with all species except P. falciparum appearing to exhibit a combination of characteristics which are able to selfregulate parasite density. - Funding: This work was supported by NHMRC grant #613648. MLG is supported by NHMRC CDA and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Michelle Gatton is currently an academic editor for PLOS ONE, and this does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. An ideal parasite must derive benefit without killing its host, at least until the parasite has an opportunity to reproduce. Parasites causing malaria invade host red blood cells (RBCs), mature and replicate within the RBC and subsequently kill these host cells as schizont stage parasites rupture, causing the lysis of the RBC and releasing merozoite stage parasites into the blood stream to start the process over. Asexual reproduction during the erythrocytic phase of the Plasmodium life cycle can thus result in an exponential increase in the number of parasites, which has the capacity to induce significant anaemia in their host. In the case of malaria in a nave host, anaemia is a major cause of morbidity, and, potentially mortality, particularly if the host is malnourished, has pre-existing anaemia or co-infections that increase the immunological burden on the host [1]. The parasite therefore must balance achieving a suitably high reproduction rate while maximising the probability the host will survive until the parasite can achieve sexual stage transmission. From the host perspective, slowing the growth rate or limiting the total number of parasites in the early stages of infection may be key to providing sufficient time to develop a specific immune response [2]. There are at least four possible strategies that parasites can adopt to regulate their reproduction, reduce the burden of infection, and ensure survival without killing the host: 1. Limit the range of RBC age classes that are able to be invaded (preferential invasion of certain RBCs). 2. Reduce the maximum parasite replication rate (i.e. produce fewer merozoites per schizont). 3. Increase the time required to complete each erythrocytic cycle. 4. Rely on the host immune response to control the parasite burden. The preferential invasion of particular RBC age classes is characteristic of some species of human malaria parasites. Plasmodium falciparum is capable of invading all RBC age classes, while P. vivax and P. ovale demonstrate a strong preference for the youngest RBCs (reticulocytes) and P. malariae the mature RBCs [1,3]. The RBC invasion preferences (if any) for P. knowlesi are still to be identified. It is generally accepted that P. falciparum is predominantly responsible for cases of severe disease and malariarelated mortalities, while the other human Plasmodium species, which are more discerning in the RBCs they invade, are relatively more benign disease agents [4]. While the severe complications associated with P. falciparum are not generally directly related to anaemia, the ability to achieve high parasite densities facilitates the development of conditions such as cerebral malaria [1,4]. However, there are currently limited data on parasite dynamics and the loss of RBCs following infection in humans [5]. It has previously been posited that there is a relationship between disease severity and the age classes of erythrocytes infected, such that parasites which only target particular age classes are less likely to be associated with severe disease [6]. A preference for invasion of a limited selection of RBCs by merozoites (either through specific targeting of particular age classes or because other potential host cells are more difficult to invade [2]) may increase competition between merozoites for suitable host cells and will ultimately limit parasite numbers, in a manner not dissimilar to logistic population growth. In natural populations, the logistic growth model posits that competition for limited resources places an artificial cap on abundance [7]. Similarly, a strong restriction to RBCs of a particular age class may diminish the pool of susceptible host RBCs, reducing the number of merozoites able to successfully find a new host cell, an idea previously proposed by a number of authors [5,8,9]. As a proportion of parasites are killed, unable to find a suitable RBC to invade, the virulence of an infection is diminished, allowing time for an appropriate specific immune response to be established [2]. Conversely, modelling work has suggested that depletion of the reticulocyte population by the unchecked growth of a P. vivax infection can be detrimental to the host and result in severe disease outcomes [10]. In the absence of a host immune response, the constant removal of reticulocytes shortly after their introduction into the system can be catastrophic; new RBCs are continually destroyed while the older RBCs they are intended to replace naturally senesce, leading to a reduction in RBC abundance in all age classes. This contrasts with a P. falciparum infection, where losses are spread across a wider range of RBC age classes, so no particular class is subjected to heavy depletion, and some new cells are able to survive and replace older RBCs naturally leaving the system. Anothe (...truncated)