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?falciparum in humans from that in gorillas [7,46], and making P.?falciparum Alectinib an ancient outbreak in humans [47�C49]. More recently, a strain similar to P.?falciparum has been reported in an African pet monkey (Cercopithecus nictitans) [50], and the authors argued that this finding challenged the gorilla origin of the human P.?falciparum parasite (i.e. African non-ape primate origin). Unfortunately, this finding has been controversial, being not well enough supported by the data [51]. These potential host switches highlight, rather, a significant adaptive capacity of Laverania parasites to adapt to new, non-natural hosts. Until recently, it was assumed that P.?falciparum and P.?reichenowi (the only close relative of P.?falciparum known and molecularly characterized) had evolved from a common ancestor parasite, independently in their respective hosts, humans and chimpanzees, as these two lineages have gradually diverged from one another over the last 5�C7?million years, i.e. the co-speciation hypothesis. The new findings on malarial parasites in Tryptophan synthase apes challenged this initial co-speciation hypothesis, suggesting an alternative hypothesis for the origin of the malignant human malarial parasite, i.e. a gorilla origin of human P.?falciparum. On the basis of comparison of mitochondrial DNA sequences from human P.?falciparum strains and malarial parasites closely related to human P.?falciparum strains in gorillas, Baron et?al. [47] subsequently revised the age estimates of P.?falciparum infection in humans to between 1?million and 112?000?years. Currently, P.?falciparum appears to be the only Laverania parasite that is able to infect humans; experimental infections with P.?reichenowi in humans have failed [1]. The invasion of RBCs by P.?reichenowi and P.?falciparum depends mostly on the interaction of erythrocyte-binding antigen -175 on malarial merozoites with glycophorins, which are sialic acid-containing glycoproteins on the surfaces of RBCs (Fig.?2). N-Glycolylneuraminic acid is a sialic acid expressed in apes and absent in human tissues, because PI3K inhibitor drugs of inactivation of the gene encoding CMP-N-acetylneuraminic acid hydroxylase [52,53]. Human DNA contains a 92-bp deletion, resulting in a frameshift mutation that prevents the production of N-glycolylneuraminic acid, and that leads to the accumulation of its precursor, N-acetylneuraminic acid (Neu5Ac). Both molecular and fossil explorations (Neanderthals did not have the enzyme needed to convert Neu5Ac) are congruent in indicating the time of appearance of this mutation to be around 2?million years ago [54]. It is hypothesized that Lavarania malaria could be the main selective pressure resulting in the fixation of this allele in the entire human population.
