Recurrent Parasitemias and Population Dynamics of Plasmodium vivax Polymorphisms in Rural Amazonia

Abstract

Abstract. Clinical trials documented alarming post-treatment Plasmodium vivax recurrence rates caused by recrudescence of surviving asexual blood stages, relapse from hypnozoites, or new infections. Here we describe high rates of P. vivax recurrence (26-40% 180 days after treatment) in two cohorts of rural Amazonians exposed to low levels of malaria transmission after a vivax malaria episode treated with chloroquine-primaquine. Microsatellite analysis of 28 paired acute infection and recurrence parasites showed only two pairs of identical haplotypes (consistent with recrudescences or reactivation of homologous hypnozoites) and four pairs of related haplotypes (sharing alleles at 11-13 of 14 microsatellites analyzed). Local isolates of P. vivax were extraordinarily diverse and rarely shared the same haplotype, indicating that frequent recurrences did not favor the persistence or reappearance of clonal lineages of parasites in the population. This fast haplotype replacement rate may represent the typical population dynamics of neutral polymorphisms in parasites from low-endemicity areas.

Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

“…Parasites were systematically sampled over 30 months (April 2004 through October 2006) in one of the study sites in Brazil, Granada [11,16]. We hypothesized that local parasite populations gradually diversify over time as a result of migration, genetic drift, mutation and recombination.…”

“…The 249 samples from Brazil were collected in the rural settlement of Granada and the town of Plácido de Castro (50 km south of Granada), both in Acre State, and in the city of Porto Velho (500 km east of Granada), in Rondônia State. The samples from Granada (n = 193) were collected during prospective cohort studies between 2004 and 2006 [11,16,30], those from Plácido de Castro (n = 38) were collected in 2008 from patients attending the town's malaria clinic [31], and those from Porto Velho (n = 17) were collected from patients attending the Oswaldo Cruz Outpatient Clinic in June-July 1995 [32]. The 70 samples from Cambodia were collected between June and December 2008 in Pursat town from individuals who became infected in the nearby forests (ClinicalTrials.gov identifier, NCT00663546).…”

Microgeographical Differences of Plasmodium vivax Relapse and Re-Infection in the Peruvian Amazon

“…33 We have shown that by adding more polymorphic markers into the analysis, the proportion if identical genotypes may be even lower than what we found with msp3-alpha. For example, a similar study in Brazil 34 has found very few 14-marker haplotypes in recurrent P. vivax infections using microsatellite typing. In this study, we considered a 5% tolerance in band sizes for TR markers to consider the possibility that relapsing parasites may be a minor, genetically different parasite clone that could have missed when typing parasites at the reference infection.…”

Molecular markers and genetic diversity of Plasmodium vivax

“…In contrast to the ~1,000 polymorphic microsatellite loci currently available for P. falciparum typing, it was demonstrated that a few dozen microsatellite loci are polymorphic in P. vivax field isolates (Table II). Despite these limitations, microsatellite-based studies of the parasite have provided valuable information on P. vivax population structure and diversity in the Americas, Asia and Africa (Ferreira et al 2007, Karunaweera et al 2007, Koepfli et al 2009, Orjuela-Sánchez et al 2009a, Gunawardena et al 2010, Rezende et al 2010, Van den Eede et al 2010a, b, 2011). …”

“…For example, in 90 P. vivax isolates from Thailand, Cui et al (2003b) found a multiple-clone infection rate of 25.6% using the PvCSP encoding gene alone, 19.3% using PvMSP-3α alone and 35.6% when the markers were combined. Particularly surprising is the extensive clonal diversity of P. vivax infections in areas with relatively low malaria transmission, such as Brazil, Colombia and Sri Lanka (Ferreira et al 2007, Imwong et al 2007b, Karunaweera et al 2008, Orjuela-Sánchez et al 2009a, Gunawardena et al 2010. The evolutionary and epidemiological consequences of multiple-clone P. vivax infections have not been well-investigated.…”