Abstract

Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5′ ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct.

Highlights

  • Antigenic variation in pathogens is an adaptation to protective host immunity

  • This study reveals a history of constant innovation in Babesia genomes with respect to genes implicated in antigenic variation, and, in so doing, we have discovered that novel ves-like gene families, thought to be secreted, have been independently derived from canonical ves1 genes in different species

  • Gene number and the proportion of coding sequences are related to the quality of sequence assemblies and sequence contiguity, which is lower in sequences produced from short reads only

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Summary

Introduction

Antigenic variation in pathogens is an adaptation to protective host immunity. It describes the serial replacement of variant antigens situated on the pathogen surface during an infection, causing the negation of immune responses mounted to the preceding antigen. Antigenic variation is a tangible expression of the coevolutionary arms race between hosts and pathogens and has evolved on several occasions in diverse lineages [1]. This includes the etiological agents of prominent diseases of humans and animals, such as malaria [2], trypanosomiasis [3,4], influenza [5], bacterial meningitis [6] and anaplasmosis [7]. Since antigenic variation is fundamental to circumventing the immune response, it plays a central role in pathogenesis and virulence and is one of the main obstacles to developing effective vaccines [8,9,10]

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