Abstract
Studies of Plasmodium falciparum invasion pathways in field isolates have been limited. Red blood cell (RBC) invasion is a complex process involving two invasion protein families; Erythrocyte Binding-Like (EBL) and the Reticulocyte Binding-Like (PfRh) proteins, which are polymorphic and not fully characterized in field isolates. To determine the various P. falciparum invasion pathways used by parasite isolates from South America, we studied the invasion phenotypes in three regions: Colombia, Peru and Brazil. Additionally, polymorphisms in three members of the EBL (EBA-181, EBA-175 and EBL-1) and five members of the PfRh (PfRh1, PfRh2a, PfRh2b, PfRh4, PfRh5) families were determined. We found that most P. falciparum field isolates from Colombia and Peru invade RBCs through an atypical invasion pathway phenotypically characterized as resistant to all enzyme treatments (NrTrCr). Moreover, the invasion pathways and the ligand polymorphisms differed substantially among the Colombian and Brazilian isolates while the Peruvian isolates represent an amalgam of those present in the Colombian and Brazilian field isolates. The NrTrCr invasion profile was associated with the presence of the PfRh2a pepC variant, the PfRh5 variant 1 and EBA-181 RVNKN variant. The ebl and Pfrh expression levels in a field isolate displaying the NrTrCr profile also pointed to PfRh2a, PfRh5 and EBA-181 as being possibly the major players in this invasion pathway. Notably, our studies demonstrate the uniqueness of the Peruvian P. falciparum field isolates in terms of their invasion profiles and ligand polymorphisms, and present a unique opportunity for studying the ability of P. falciparum parasites to expand their invasion repertoire after being reintroduced to human populations. The present study is directly relevant to asexual blood stage vaccine design focused on invasion pathway proteins, suggesting that regional invasion variants and global geographical variation are likely to preclude a simple one size fits all type of vaccine.
Highlights
Malaria remains an important public health problem in the developing world
To begin to understand the geographic differentiation of P. falciparum invasion, phenotypically and genetically, we studied invasion phenotypes of Colombian, Peruvian and Brazilian field isolates into enzymetreated Red blood cell (RBC), and compared them to those described in Africa and India
Invasion into trypsin-treated RBCs was associated with invasion into chymotrypsin-treated RBCs (p = 0.037; rs = 0.375; Spearman’s correlation) (Figure S1), suggesting that many parasites use simultaneously invasion pathways that are dependent on receptors resistant to both enzymes
Summary
Malaria remains an important public health problem in the developing world. In 2010, there were an estimated 216 million cases of malaria worldwide, of which 91% were due to Plasmodium falciparum [1]. While the vast majority of malaria cases occur in sub-Saharan Africa, the disease is a public health problem in more than 109 countries [1]. Malaria transmission in South America, typically characterized as hypoendemic and unstable, places approximately 170 million inhabitants on the continent at risk of malaria infection [1]. Sixty percent of the malaria cases occur in Brazil (Amazonian region) and the remaining 40% are distributed among 20 other Central and South America countries [2]. It has been proposed that European colonization led to the introduction of P. falciparum to South America. P. falciparum was reintroduced to Peru in the 1990s reaching epidemic levels after 1995 [5]; it was eradicated in Peru by the late 1980s with no new cases reported until the early 1990s [6,7]
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