Networks of genetic similarity reveal non-neutral processes shape strain structure in Plasmodium falciparum

Abstract

Pathogens compete for hosts through patterns of cross-protection conferred by immune responses to antigens. In Plasmodium falciparum malaria, the var multigene family encoding for the major blood-stage antigen PfEMP1 has evolved enormous genetic diversity through ectopic recombination and mutation. With 50–60 var genes per genome, it is unclear whether immune selection can act as a dominant force in structuring var repertoires of local populations. The combinatorial complexity of the var system remains beyond the reach of existing strain theory and previous evidence for non-random structure cannot demonstrate immune selection without comparison with neutral models. We develop two neutral models that encompass malaria epidemiology but exclude competitive interactions between parasites. These models, combined with networks of genetic similarity, reveal non-neutral strain structure in both simulated systems and an extensively sampled population in Ghana. The unique population structure we identify underlies the large transmission reservoir characteristic of highly endemic regions in Africa.

The network structure and eco-evolutionary dynamics of CRISPR-induced immune diversification

“…Its emergence from immune selection was demonstrated here. It is consistent with existing strain theory developed mostly for human infections and pathogens with multilocus encoding of antigens, when evolution is considered explicitly [11,12,15,54]. Immune selection acts as a form negative frequency-dependent selection creating groups of pathogens with limiting overlap in antigenic space.…”

“…In the absence of data on immunity of hosts, this pattern has been described as modules, or clusters, in networks that depict genetic similarity between the pathogens themselves [11,12]. This outcome is conceptually analogous to groups of species or microbes coexisting under frequency-dependent competition for resources [55].…”

“…The Gillespie algorithm was originally conceived for chemical reactions [69] and is now widely used in epidemiology and ecology (e.g. [11,14,15,30]). The basic algorithm consists of three steps: (1) determination of the random time to the next reaction (also termed 'event'); (2) random selection of a specific event from a set of events using weighted sampling (events with higher rates are more likely to be chosen); and (3) updating the number of chemical molecules (in our case, host or virus strains) involved in the selected event.…”

“…Infection structure should critically depend however on the genetic basis of resistance of hosts to pathogens [10]. The emergence of network structure from immune selection has been shown in pathogens of humans such as Plasmodium falciparum [11,12]. In particular, strain theory developed for pathogens with multilocus encoding of antigens posits that negative frequency dependent selection, mediated by competition for hosts through cross-immunity, can structure pathogen populations into clusters of strains with limited overlap of antigenic repertoires [11][12][13][14][15].…”

Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in Plasmodium falciparum

“…Theoretical studies for low-to-medium genetic diversity predicted parasite strains with no, or limited, genetic overlap [12,13], including in the case of multicopy genes [14]. For P. falciparum, recent work allowing for realistic levels of genetic diversity comparable to that found in endemic high transmission regions of sub-Saharan Africa, resulted in a more complex similarity structure clearly distinguishable from patterns generated under neutrality but that can no longer be described by distinct clusters [15]. Deep sampling and sequencing of var gene isolates from asymptomatic human populations within a given time window or transmission season, have confirmed these non-random patterns that are also non-neutral, in the sense that they cannot be simply explained by stochastic extinction, immigration, and transmission in the absence of acquired immune memory and therefore, competition of parasites for hosts [15][16][17].…”