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Title: Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum}
Article:
Abstract:
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.
Introduction:
Many pathogen populations seem to be composed of several independent strains; this has important implications for disease surveillance and control, as well as for the identification of vaccine targets. In particular, the population genetic interactions between pathogen strains can have significant epidemiological consequences, influencing transmissibility, clinical immunity, and the duration and severity of infection. An extensive variety of microparasites have been studied in this context: protozoa, such as Plasmodium falciparum, Leishmania, and Trypanosoma brucei; viruses, such as Influenza, HIV and Dengue; and bacteria, such as E. coli, Bordetella spp. and Neisseria meningitides( Tibayrenc et al., 1990; Gupta et al., 1994; Tibayrenc and Ayala, 2002). The conceptual challenges and significant human health implications associated with the pathogen population structure have led to the establishment of several theories for why we observe this structure in nature( Selander et al., 1987; Tibayrenc et al., 1990; Smith et al., 1993; Gupta and Day, 1994a, 1994b; Gupta et al., 1996; Tibayrenc, 1994). In particular, while it would seem that sufficient out-crossing should always lead to random associations between alleles( Tibayrenc et al., 1990; Tibayrenc and Ayala, 2002) and preclude the persistence of ‘independently transmitted strains’( Tibayrenc, 1994), mathematical models of competition between pathogen strains have demonstrated that immune selection can lead to the maintenance of discrete, non-overlapping, antigenic repertoires—even when antigenic variability is driven by several unlinked genes that undergo recombination( Gupta et al., 1996; Gupta and Anderson, 1999). An inherent challenge in testing ‘strain theory’ is to determine whether observed empirical patterns in pathogen population structure result from immune selection, or alternatively, from simple demographic processes( i. e., uneven relatedness among individuals in the pathogen population that can result from random genetic drift, particularly within the complex context of transmission dynamics)( Buckee et al., 2008, 2011). P. falciparum is responsible for the deadliest type of malaria in humans. The complexities of its population genetics, in terms of the variable and often enormous levels of sequence variation observed at antigenic sites within local populations, are intimately tied to both its pathology and its ability to escape immune detection. While this genetic complexity provides significant challenges to malaria research and control, it also provides an opportunity to extend existing strain theory in a way that can be tested empirically. Specifically, an important extension of earlier strain theory is to consider the effects of immune selection in populations of pathogens whose antigen-encoding loci are:( a) multi-copy and recombining( i. e., located on different chromosomes of a haploid genome), and( b) undergoing antigenic variation via sequential, mutually exclusive expression within an infected host. It is not clear whether a stable strain structure would emerge under the sequential expression of multi-copy genes. Consideration of this type of system provides a more complete framework for understanding antigenic structure and its epidemiological consequences in a broader variety of pathogens; it also offers the opportunity to distinguish the effects of immune selection from those of neutral demographic forces, providing testable predictions for these two alternative mechanisms. We describe an agent-based model that extends strain theory to address the effect of immune selection acting on multi-copy antigen genes; we use the var gene family of P. falciparum as the basis for this model. The var genes encode P. falciparum erythrocyte membrane protein 1( PfEMP1)—the major surface antigen of the parasite's blood stages that binds to host endothelial cell receptors to allow the parasite to sequester within various host tissues( Miller et al., 2002; Scherf et al., 2008). Var genes are composed of multiple Duffy-binding-like( DBL) and cysteine-interdomain-rich( CIDR) domains that encode binding functions for specific endothelial receptors. DBLα, is the only domain found in nearly all var genes( Miller et al., 2002), and hence is the most informative molecular marker of var gene diversity. Each parasite genome has up to 60 var genes, and differential sequential expression of these genes allows the parasite to evade the host immune response and establish a chronic infection. This clonal antigenic variation sensu stricto( Miller et al., 2002; Scherf et al., 2008) extends the duration of infection to facilitate transmission to the mosquito. Not only do var genes influence transmission, but specific var genes are associated with severe malarial disease and specific PfEMP1 binding phenotypes( Deitsch et al., 2009; Chan et al., 2012; Claessens et al., 2012; Lavstsen et al., 2012; Warimwe et al., 2012). Population studies have shown that individual P. falciparum genomes have distinct repertoires of var genes( Barry et al., 2007; Scherf et al., 2008; Chen et al., 2011) that extensively recombine( Freitas-Junior et al., 2000; Taylor et al., 2000) during sexual recombination in the mosquito( Paul et al., 1995). The immense sequence diversity observed among var genes and var repertoires has been attributed to high rates of meiotic( and possibly also mitotic) recombination. These high rates of recombination presumably allow for very low linkage disequilibrium among var loci. Our modeling framework considers the dynamics shaping the enormous potential diversity of genomic repertoires of var genes by tracking all possible var repertoires, given a diverse pool of genetic variants. We explore whether structured parasite populations resulting from the selection pressures exerted by competition among distinct var repertoires for hosts, mediated by cross-immunity, can emerge.
Discussion:
In accordance with predictions from the original ‘strain theory’, our model constrains total repertoire diversity to levels that are orders of magnitude lower than is potentially possible given the diversity of the gene pool. This reduction in diversity occurs because coexisting parasites are structured into a few variants with largely discordant repertoires. In a departure from previous strain theory, our model predicts that the different dominant repertoires can exhibit partial overlap; the extent of the overlap increases with transmission intensity and this, in turn, influences observed epidemiological patterns( particularly age-serology profiles). The specific immune profile of each individual host effectively structures the population into distinct sets of ‘patches’ or ‘resources’ that define an immune environment, ultimately causing immune selection to act on the parasite population. These distinct sets of patches are formed and conserved even when immunity to the var alleles is shorter-lived. Observations of individuals becoming susceptible to severe infection at later stages of their life( see for example( Dhingra et al., 2010)), may be in part a consequence of short-lived immunity. Under this assumption, hosts in our model regain protection by exposure to one of the dominant strains circulating in the host population at high frequencies, and do so at a sufficiently high rate to preserve strain population structure except at extremely low transmission intensity. In the event that a host is infected by one of the low frequency genomes that are continuously being introduced( and equally quickly vanishing), it is highly unlikely that this successful transmission event is sufficient for invasion or even replacement of the currently dominating strain community. Discordant repertoires that exhibit partial immunological/antigenic overlap blur the distinction between the acquisition of strictly strain-specific immunity and the acquisition of strictly strain-transcending immunity( Gupta and Day, 1994a, 1994b)( see caption of Figure 5). This underscores the role of strain diversity structure, rather than diversity per se, in determining observed epidemiological patterns and their response to intervention. By reducing antigenic overlap between strains, vector control efforts will result in infection at an older age and a more gradual acquisition of protection to infection, even in the absence of changes in var gene diversity. The model in its current form does not differentiate infection from clinical disease, thus we cannot explicitly address the impact of control on the severity of symptoms. However, if the number of var genes that a host has previously encountered relates to the degree of protection against clinical disease, we would expect more severe symptoms to occur at younger ages under high transmission settings, and in contrast, more homogeneous malaria incidents are likely to occur over a broader range of age-classes when transmission is lowered( Figure 4D). Investigation of these patterns awaits the formulation of models that include functional, non-antigenic, differences between strains, as well as more empirical understanding of the role played by var genes associated with more severe disease. Future work should thus extend our model to consider functional, non-antigen-encoding differences between var genes( Bull et al., 1999; Miller et al., 2002; Scherf et al., 2008; Buckee et al., 2009; Claessens et al., 2012; Severins et al., 2012 for an example of a recent model applied to questions on the evolution of virulence). Ultimately, ways to represent the effects of pathogen diversity implicitly within a standard epidemiological framework, that might also be more easily parameterized, should also be investigated. The goal of malaria eradication is to reduce the reservoir of malaria infection in humans to zero. Chen et al.( 2011) have pointed to the importance of var genes in malaria surveillance, due to their influence on both the duration of infection and the degree of superinfection, and they demonstrated the existence of an immense diversity of var genes and limited var repertoire overlap in Africa, even in sites with low malaria prevalence. Consequently, they have proposed that var typing be used to complement prevalence measures for molecular surveillance of malaria control and elimination efforts. Our models support this proposal as they show that decreasing transmission provokes nonlinear changes in the dominant var configurations. Importantly, our results demonstrate that there is not a simple relationship between var diversity and repertoire diversity. Indeed, the ‘var strain’ model suggests that vector control strategies that reduce transmission will not always drastically reduce var gene diversity, because a reservoir of parasite genomes with diverse( highly non-overlapping) var repertoires will remain. This insight from the model provides a plausible explanation for why it is so difficult to eliminate malaria: non-overlapping var diversity will create significant inherent difficulties in reducing the potential of the malaria parasite to reinfect the same hosts. It also suggests that var surveillance might provide a good molecular means of evaluating control. If the end game is to be achieved in malaria control, then the mechanisms creating and maintaining antigenic diversity warrant further investigation in both modeling and empirical studies. In conclusion, the results of our model on the dynamics of population structure in P. falciparum as defined by the var multi-gene family, have broad implications for the possible emergence of similar structure in many important human and animal pathogens that have major surface antigens encoded by multigene families, including bacterial, protozoan and fungal pathogens( Deitsch et al., 2009).
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 .