Complement Receptor 1 availability on red blood cell surface modulates Plasmodium vivax invasion of human reticulocytes

Abstract

Plasmodium vivax parasites preferentially invade reticulocyte cells in a multistep process that is still poorly understood. In this study, we used ex vivo invasion assays and population genetic analyses to investigate the involvement of complement receptor 1 (CR1) in P . vivax invasion. First, we observed that P . vivax invasion of reticulocytes was consistently reduced when CR1 surface expression was reduced through enzymatic cleavage, in the presence of naturally low-CR1-expressing cells compared with high-CR1-expressing cells, and with the addition of soluble CR1, a known inhibitor of P . falciparum invasion. Immuno-precipitation experiments with P . vivax Reticulocyte Binding Proteins showed no evidence of complex formation. In addition, analysis of CR1 genetic data for worldwide human populations with different exposure to malaria parasites show significantly higher frequency of CR1 alleles associated with low receptor expression on the surface of RBCs and higher linkage disequilibrium in human populations exposed to P . vivax malaria compared with unexposed populations. These results are consistent with a positive selection of low-CR1-expressing alleles in vivax-endemic areas. Collectively, our findings demonstrate that CR1 availability on the surface of RBCs modulates P . vivax invasion. The identification of new molecular interactions is crucial to guiding the rational development of new therapeutic interventions against vivax malaria.

Three Signatures of Adaptive Polymorphism Exemplified by Malaria-Associated Genes

“…2012 ), CR1 (Knops blood group; Tham et al. 2010 ; Prajapati et al. 2019 ), HBB (hemoglobin B; Allison 1954 ; Laval et al.…”

Three hallmarks of malaria-induced selection in human genomes

“…It is unclear why Duffy-null did not also spread widely beyond Africa, but instead P. vivax in Asia selected for a different ACKR1 allele, Fy a (King et al 2011; Chittoria et al 2012). CR1 shows a similar signature of parallel evolution and impacts resistance to both P. vivax (Prajapati et al 2019) and P. falciparum (Tham et al 2010), suggesting that either or both of these species may have driven its evolution. Third, Arrested Sweeps are the most recent evolutionary scenario and are associated with the expansion of P. falciparum, which likely dispersed across sub-Saharan Africa along with agriculture, which facilitates optimal mosquito habitat, during the past few thousand years.…”

“…This is due to near-fixation of the Duffy-null allele in sub-Saharan Africa, and independent selection for the Fy a allele in Asia (Hamblin et al 2002; King et al 2011; Chittoria et al 2012). Similarly, CR1 is also divergent in both Africa-Europe and Asia-Europe comparisons due to positive selection (Prajapati et al 2019). Our previous genome-wide scan for parallel adaptive divergence (Tennessen and Akey 2011) sought repeated, phylogenetically independent shifts occurring at the same single-nucleotide variant among a set of four populations.…”

“…Bolstered by the intimate coevolutionary history between humans and Plasmodium and the severe pathology of malaria, several of the strongest signatures of selection in the human genome center on genes that impact malaria resistance. These genes include ABO (A/B/O blood group; Ségurel et al 2012, 2013), the cluster of GYPA, GYPB , and GYPE (here abbreviated to GYPA/B/E , glycophorin Dantu blood group; Leffler et al 2017), ACKR1 (Duffy antigen; Hamblin et al 2002; King et al 2011; Chittoria et al 2012), CR1 (Knops blood group; Tham et al 2010; Prajapati et al 2019), HBB (hemoglobin B; Allison 1954; Laval et al 2019), and G6PD (glucose-6-phosphate dehydrogenase; Ruwende et al 1995; Tishkoff et al 2001). Malaria remains a major selection pressure to this day, with 200 million cases annually, leading to over 400,000 deaths (Miller et al 2002; WHO 2019).…”

The enigmatic mechanisms by which Plasmodium vivax infects Duffy-negative individuals

“…However, as mentioned before, there is still no continuous in vitro culture for this parasite species, and consequently no genetic transformation is possible. Only tedious, short-term cultures conducted in a handful of laboratories around the world can be performed [76,[93][94][95]. Nevertheless, using those assays in order to evaluate the capacity of parasites with different genotypes (i.e., single or multicopy pvdbp parasites) to invade Duffynegative reticulocytes in presence or absence of monoclonal antibodies specific for a candidate ligand or receptor will allow one to determine the pathways used by P. vivax to infect Duffynegative erythrocytes.…”