Pathogen escape from host immunity by a genome program for antigenic variation

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Abstract
The vector-borne bacterium Borrelia hermsii, a relapsing fever agent, switches gene expression of a surface protein between different antigenic variants, thereby causing sequential waves of immune escape within hosts and increasing the likelihood of transmission. Analogous programmed systems of antigenic variation occur in African trypanosomes and Plasmodium falciparum. In these examples, switch rates to individual variants differ over a wide range. We studied how B. hermsii determines switch rates in two experimental infections: one where variants were identified by specific antisera and one based on identification by DNA sequence. Unexpressed loci of variant antigens copy into a single expression site at rates determined by extragenic features of silent loci rather than similarity between coding sequences of variants at silent sites and the single expression site. Two elements, in particular, determine switch rates. One set of elements overlaps the 5′ ends of the expressed gene and the silent loci; greater sequence identity between elements was associated with a higher switch rate. The second set of elements flanks the expression site on the 3′ side and occurs at variable distances downstream from silent loci; the nearer an element to a silent locus, the greater the switch rate of that locus into the expression site. In combination, these two features of the genome provide a simple mechanism to modulate switch rate whereby silent loci form a hierarchy of switch rates into the expression site. Although the switching hierarchy causes changes in individual cells that are stochastic, ordering of variants within hosts is semipredictable.