African trypanosomes expressing multiple VSGs are rapidly eliminated by the host immune system.

Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of variant surface glycoprotein (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection, in terms of antibody response and disease severity, remain unknown. In this study, we overexpressed a high-mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression, and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed prolonged survival in which nearly 90% of the mice survived a 30-d period of infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reducing disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental to the parasite, even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.

Aresta-Branco F ，Sanches-Vaz M ，Bento F ，Rodrigues JA ，Figueiredo LM ... -  《-》

Variant surface glycoprotein density defines an immune evasion threshold for African trypanosomes undergoing antigenic variation.

Pinger J ，Chowdhury S ，Papavasiliou FN 《Nature Communications》

A Host-Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei.

Hovel-Miner G ，Mugnier M ，Papavasiliou FN ，Pinger J ，Schulz D ... -  《-》

Quantitative sequencing confirms VSG diversity as central to immune evasion by Trypanosoma brucei.

Antigenic variation is central to the virulence of African trypanosomes, where the VSG coat is used to evade the host immune system. Recent advances in technology have now allowed more secrets of this system to emerge, with the surprising insight that a broad repertoire of VSGs is rapidly expressed. This has major implications for how the parasite must evade the host immune response.

McCulloch R ，Field MC 《-》

The in vivo dynamics of antigenic variation in Trypanosoma brucei.

Trypanosoma brucei, a causative agent of African Sleeping Sickness, constantly changes its dense variant surface glycoprotein (VSG) coat to avoid elimination by the immune system of its mammalian host, using an extensive repertoire of dedicated genes. However, the dynamics of VSG expression in T. brucei during an infection are poorly understood. We have developed a method, based on de novo assembly of VSGs, for quantitatively examining the diversity of expressed VSGs in any population of trypanosomes and monitored VSG population dynamics in vivo. Our experiments revealed unexpected diversity within parasite populations and a mechanism for diversifying the genome-encoded VSG repertoire. The interaction between T. brucei and its host is substantially more dynamic and nuanced than previously expected.

Mugnier MR ，Cross GA ，Papavasiliou FN 《-》