DNA damage drives antigen diversification through mosaic Variant Surface Glycoprotein (VSG) formation in<i>Trypanosoma brucei</i>

Smith, Jaclyn E.; Wang, Kevin J.; Kennedy, Erin M.; Hakim, Jill M.C.; So, Jaime; Beaver, Alexander K.; Magesh, Aishwarya; Gilligan-Steinberg, Shane D.; Zheng, Jessica; Zhang, Bailin; Moorthy, Dharani Narayan; Akin, Elgin Henry; Mwakibete, Lusajo; Mugnier, Monica R.

doi:10.1101/2024.03.22.582209

Cited by 2 publications

(1 citation statement)

References 93 publications

(98 reference statements)

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“…To be sure that the increased VSG diversity we observed in tissues was not due to the derepression of silent VSGs within individual cells, we performed single-cell RNA sequencing using the SL-Smart-seq3xpress platform to quantify VSG expression in single cells from blood and tissue samples 33 . Because T. brucei can form new "mosaic" VSGs through recombination 4,8,16,34 , which are, by definition, absent from reference genomes, we initially used our VSG-Seq pipeline to de novo assemble VSGs in each cell. This approach accounts for the possibility that expressed VSGs might be absent from the reference genome, either as a result of mosaic VSG formation or as a result of an incomplete genome assembly, potentially affecting quantification and/or read mapping.…”

Section: Extravascular Spaces Contain Most Of the Vsg Diversitymentioning

confidence: 99%

Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

Beaver

Crilly

Hakim

et al. 2022

Preprint

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Trypanosoma brucei lives an entirely extracellular life cycle in its mammalian host, facing a constant onslaught of host antibodies. The parasite evades clearance by the host immune system through antigenic variation of its dense variant surface glycoprotein (VSG) coat, periodically "switching" expression of the VSG using a large genomic repertoire of VSG-encoding genes. Studies of antigenic variation in vivo have focused exclusively on parasites in the bloodstream, but recent work has shown that many, if not most, parasites are extravascular and reside in the interstitial spaces of tissues. However, it is unknown whether parasites undergo antigenic variation while in extravascular spaces. We sought to explore the dynamics of antigenic variation in extravascular parasite populations using VSG-seq, a high-throughput sequencing approach for profiling VSGs expressed in populations of T. brucei. Our experiments show that the expressed VSG repertoire is not uniform across populations of parasites within the same infection and that a greater number of VSGs are expressed in tissue spaces than in the blood. More than 75% of the VSGs detected in an animal were found exclusively within extravascular spaces. Interestingly, we also noticed a delay in the VSG-specific clearance of parasites in tissue spaces compared to the blood. This finding aligns with a model in which parasites "hide" from the immune system in tissue spaces, where a slower immune response provides them with more time to generate new antigenic variants. Overall, our results show that extravascular spaces are significant reservoirs of VSG diversity, potentially resulting from delayed clearance of tissue-resident parasites.

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Section: Extravascular Spaces Contain Most Of the Vsg Diversitymentioning

confidence: 99%

Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

Beaver

Crilly

Hakim

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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Tissue spaces are reservoirs of antigenic diversity for Trypanosoma brucei

Beaver,

Keneskhanova,

Cosentino

et al. 2024

Nature

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The protozoan parasite Trypanosoma brucei evades clearance by the host immune system through antigenic variation of its dense variant surface glycoprotein (VSG) coat, periodically ‘switching’ expression of the VSG using a large genomic repertoire of VSG-encoding genes1–6. Recent studies of antigenic variation in vivo have focused near exclusively on parasites in the bloodstream6–8, but research has shown that many, if not most, parasites reside in the interstitial spaces of tissues9–13. We sought to explore the dynamics of antigenic variation in extravascular parasite populations using VSG-seq7, a high-throughput sequencing approach for profiling VSGs expressed in populations of T. brucei. Here we show that tissues, not the blood, are the primary reservoir of antigenic diversity during both needle- and tsetse bite-initiated T. brucei infections, with more than 75% of VSGs found exclusively within extravascular spaces. We found that this increased diversity is correlated with slower parasite clearance in tissue spaces. Together, these data support a model in which the slower immune response in extravascular spaces provides more time to generate the antigenic diversity needed to maintain a chronic infection. Our findings reveal the important role that extravascular spaces can have in pathogen diversification.

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DNA damage drives antigen diversification through mosaic Variant Surface Glycoprotein (VSG) formation inTrypanosoma brucei

Cited by 2 publications

References 93 publications

Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

Tissue spaces are reservoirs of antigenic diversity for Trypanosoma brucei

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