Malaria-driven adaptation of MHC class I in wild bonobo populations

Abstract

The malaria parasite Plasmodium falciparum causes substantial human mortality, primarily in equatorial Africa. Enriched in affected African populations, the B*53 variant of HLA-B, a cell surface protein that presents peptide antigens to cytotoxic lymphocytes, confers protection against severe malaria. Gorilla, chimpanzee, and bonobo are humans' closest living relatives. These African apes have HLA-B orthologs and are infected by parasites in the same subgenus (Laverania) as P. falciparum, but the consequences of these infections are unclear. Laverania parasites infect bonobos (Pan paniscus) at only one (TL2) of many sites sampled across their range. TL2 spans the Lomami River and has genetically divergent subpopulations of bonobos on each side. Papa-B, the bonobo ortholog of HLA-B, includes variants having a B*53-like (B07) peptide-binding supertype profile. Here we show that B07 Papa-B occur at high frequency in TL2 bonobos and that malaria appears to have independently selected for different B07 alleles in the two subpopulations.

Fig. 1. African ape ranges, bonobo study sites, and presence of Laverania.

a The ranges of bonobos (Pan paniscus, yellow), western chimpanzees (Pan troglodytes verus, green), Nigeria-Cameroonian chimpanzees (P. t. ellioti, purple), central chimpanzees (P. t. troglodytes, orange), eastern chimpanzees (P. t. schweinfurthii, red), western gorillas (Gorilla gorilla, cross hatch), and eastern gorillas (Gorilla beringei, single hatch) are shown. Laverania parasites have been detected in all African ape species, except the Eastern gorilla. Range data were obtained from the IUCN Red List^–. b The bonobo range (yellow) is shown in relation to the Congo, Lualaba, and Lomami Rivers (thick dark blue lines). Parallel lines mark the Boyoma Falls, a potential crossing point of the bonobo common ancestor^,. Two-letter codes indicate the bonobo study sites. TL2-W bonobos are physically separated from TL2-E bonobos by the Lomami River. TL2 bonobos on both sides of the river are endemically infected with Laverania (red circles). One faecal sample collected at KR contained P. lomamiensis.

Fig. 2. Papa-B allele counts, frequencies, and allotype phenotypes at 12 study sites.

For each Papa-B allele, it is noted which peptide-binding supertype that it possesses (B27 (yellow), B07 (blue), Patr-B*17:03 (17:03, brown), and whether or not it encodes a KIR epitope (either Bw4 (green) or C1 (red)). ^aKIR epitope and supertype are “Unknown.” ^bGenotyping resolved the second allele as being one of three alleles (Papa-B*01:02, 04:01, 09:02), all of which have the B07 supertype and lack a KIR epitope. ^cFor five eastern bonobos, a second Papa-B allele could not be identified. ^dAsterisks indicate significant frequency differences between bonobo populations west and east of the Lomami River (two-tailed Fisher’s exact tests, p < 0.0001; all comparisons in Supplementary Table 5). ^eB07 phenotype distributions for each population are given in Supplementary Table 2.

Fig. 3. Frequencies of Papa-B alleles in bonobo populations.

For each field site, the number of Papa-B allotypes is shown. Unknown (Unk) second Papa-B allotypes in TL2-E and KR are indicated in black (Fig. 2). Sites with endemic Laverania infection are shown in blue font. Source data are provided as a Source Data file. a Frequencies of the three Papa-B peptide-binding supertypes are shown: B27 (yellow), B07 (blue), Patr-B*17:03 (17:03, brown). B07 is more frequent in TL2-E and TL2-W than in any western population (two-tailed Fisher’s exact tests with Bonferroni adjusted alpha levels of 0.0167 per test: TL2-E, TL2-W, p = 0.011; TL2-E, Other-West p < 0.0001; TL2-W, Other-West, p = 0.007). b Population frequencies of KIR epitopes among Papa-B (Fig. 2). KIR epitopes (either Bw4 (green) or C1 (red)) are more frequent in all western populations compared to TL2-E, which has no epitopes (None, grey). (two-tailed Fisher’s exact tests with Bonferroni adjusted alpha levels of 0.0083 per test: all pairwise comparisons, p < 0.0001).

Fig. 4. Limited variation in the LSA-1 ls6 epitope of Laverania.

Shown are amino acid sequences of the nonamer ls6 peptide for LSA-1 proteins of eight Laverania species. Sequences are listed, along with their natural host, according to their phylogenetic relatedness^,. Positions 2 and 9 (underlined) are the conserved anchor positions (highlighted black) that hold the peptide within the MHC-B peptide-binding groove. Grey highlights residues that differ from that of P. falciparum.