The coexistence of multiple independently circulating strains in pathogen populations that undergo sexual recombination is a central question of epidemiology with profound implications for control. An agent-based model is developed that extends earlier ‘strain theory’ by addressing the var gene family of Plasmodium falciparum. The model explicitly considers the extensive diversity of multi-copy genes that undergo antigenic variation via sequential, mutually exclusive expression. It tracks the dynamics of all unique var repertoires in a population of hosts, and shows that even under high levels of sexual recombination, strain competition mediated through cross-immunity structures the parasite population into a subset of coexisting dominant repertoires of var genes whose degree of antigenic overlap depends on transmission intensity. Empirical comparison of patterns of genetic variation at antigenic and neutral sites supports this role for immune selection in structuring parasite diversity.
Malaria is an infectious disease that is estimated to kill more than half a million people every year, mostly young children in Africa. It is spread by mosquitos that are infected with Plasmodium parasites that attack red blood cells in the human body. Plasmodium falciparum, the species that is responsible for most of these deaths, causes malaria by entering red blood cells and releasing antigens that travel to the surface of the cells, where they change the adhesion properties. This causes the infected red blood cells to accumulate in small blood vessels, surface capillaries or the brain, which can have severe consequences for the person infected.
P. falciparum is particularly dangerous because of its ability to vary the antigens displayed on the cell surface: this process, known as antigenic variation, helps to maintain infections for extended periods of time by allowing the antigens to stay one step ahead of the immune system (a process known as immune escape). The origins of antigenic variation lie in the fact that each P. falciparum genome has a repertoire of between 50 and 60 var genes that code for the variability of a major antigen that is responsible for immune escape in malaria. Molecular sequencing has shown that local parasite populations contain thousands of different types of var genes: hence, meiotic recombination in the mosquito can create a vast number of combinations of var repertoires.
Artzy-Randrup et al. have developed a computational model of this highly diverse and complex system to address the following question: is a local pathogen population composed of largely random and ephemeral repertoires of these genes, or is it structured into independently circulating strains? Their model goes beyond previous models by including interactions within the local host population that arise as a result of indirect competition between different strains of the pathogen for available hosts: this competition is influenced by the history of infection and, therefore, by the patterns of immunity within the host population. Previous models included within-host processes but not these higher, local population-level interactions.
The model simulates the dynamics of all the unique combinations of var genes in a population of hosts, and shows that even with high rates of reproduction, the parasite population self-organizes into a limited number of coexisting strains: the distinct var repertoires of these strains only weakly overlap, suggesting that the immune response of the host population has been partitioned into distinct niches. By investigating genetic variation at both antigenic sites and regions of the genome that do not code for antigens, Artzy-Randrup et al. suggest that immune selection—the selection imposed on var repertoires by the build up of specific immunity at the population level—plays a central role in structuring parasite diversity.
The new model should lead to a better understanding of the epidemiology of Plasmodium and other pathogens that work in similar ways, including Trypanosoma brucei (sleeping sickness), Borellia burgdorferi (Lyme disease) and Giardia lamblia (gastroenteritis), and help with global efforts to eliminate malaria and other diseases.