Evidence of strain structure in Plasmodium falciparum var gene repertoires in children from Gabon, West Africa

Abstract

Existing theory on competition for hosts between pathogen strains has proposed that immune selection can lead to the maintenance of strain structure consisting of discrete, weakly overlapping antigenic repertoires. This prediction of strain theory has conceptual overlap with fundamental ideas in ecology on niche partitioning and limiting similarity between coexisting species in an ecosystem, which oppose the hypothesis of neutral coexistence. For Plasmodium falciparum, strain theory has been specifically proposed in relation to the major surface antigen of the blood stage, known as PfEMP1 and encoded by the multicopy multigene family known as the var genes. Deep sampling of the DBLα domain of var genes in the local population of Bakoumba, West Africa, was completed to define whether patterns of repertoire overlap support a role of immune selection under the opposing force of high outcrossing, a characteristic of areas of intense malaria transmission. Using a 454 high-throughput sequencing protocol, we report extremely high diversity of the DBLα domain and a large parasite population with DBLα repertoires structured into nonrandom patterns of overlap. Such population structure, significant for the high diversity of var genes that compose it at a local level, supports the existence of "strains" characterized by distinct var gene repertoires. Nonneutral, frequency-dependent competition would be at play and could underlie these patterns. With a computational experiment that simulates an intervention similar to mass drug administration, we argue that the observed repertoire structure matters for the antigenic var diversity of the parasite population remaining after intervention.Plasmodium falciparum | var genes | parasite diversity | strain structure | Gabon

Evolutionary structure of Plasmodium falciparum major variant surface antigen genes in South America: Implications for epidemic transmission and surveillance

“…Specifically, the major P. falciparum variant surface antigen of the blood stages, Pf EMP1, is a key marker as it is a virulence factor and immunity to this antigen determines the dynamics of infection within and between hosts (e.g., (Artzy‐Randrup et al., 2012)). To date few malaria surveillance studies have used var genes encoding Pf EMP1 due to the extreme diversity and the complexity of undertaking population genetics with this multigene family (Albrecht et al., 2010; Artzy‐Randrup et al., 2012; Chen et al., 2011; Day et al., 2017; Tessema et al., 2015). Here, using the 454 high throughput sequencing approach to obtain well‐sampled populations, we show that the conserved DBLα domain of var genes constitutes a promising biomarker to infer population structure, and more generally for epidemiological disease surveillance.…”

“…The conserved var DBLα domain has previously been used as a marker for var gene diversity in other global studies (Barry et al., 2007; Chen et al., 2011; Day et al., 2017; Tessema et al., 2015). The P. falciparum var DBLα domain was amplified from genomic DNA using fusion primers for multiplexed 454 Titanium sequencing.…”

“…To define distinct DBLα types shared within and between populations, we clustered nonredundant sequences from all isolates from the South American populations by average linkage using a sequence identity threshold of 96%. This 96% cut off was chosen to define unique DBLα types as it has been previously shown to be robust at defining DBLα types with identical sequences (excluding minor sequence errors) (Day et al., 2017). …”

“…The high levels of mitotic recombination observed within cloned lines have led to a view that var genes may not be a stable marker for molecular surveillance. However, population genetic studies from malaria endemic regions like Africa, Papua New Guinea, and South America have demonstrated that sequencing the highly conserved DBLα domain of var genes is an effective approach to both characterize and monitor P. falciparum diversity spatially and longitudinally (Barry et al., 2007; Chen et al., 2011; Day et al., 2017; Scherf et al., 2008; Tessema et al., 2015). …”

Signatures of competition and strain structure within the major blood‐stage antigen of Plasmodium falciparum in a local community in Ghana

“…It is also estimated that host individuals in highly endemic areas are infected with hundreds of distinct strains of P. falciparum malaria over the course of their lives. It is poorly understood whether and how these gene variants are organized into genomic repertoires at the population level (Day et al., ). See the Information Box below for a more in‐depth discussion of var gene biology and P. falciparum malaria.…”