Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Abstract

Pathogens often persist during infection because of antigenic variation, in which they evade immunity by switching between distinct surface antigen variants. A central question is how ordered appearance of variants, an important determinant of chronicity, is achieved. Theories suggest it results directly, from a complex pattern of transition connectivity between variants, or indirectly, from effects such as immune cross-reactivity or differential variant growth rates. Using a mathematical model based only on known infection variables, we show that order in trypanosome infections can be explained more parsimoniously, by a simpler combination of two key, parasite-intrinsic factors: differential activation rates of parasite variant surface glycoprotein (VSG) genes, and density-dependent parasite differentiation. The model outcomes concur with empirical evidence that several variants are expressed simultaneously and that parasitaemia peaks correlate with VSG genes within distinct activation probability groups. Our findings provide a possible explanation for the enormity of the recently sequenced VSG silent archive and have important implications for field transmission.