Slow growing behavior in African trypanosomes during adipose tissue colonization

Trindade, Sandra; Niz, Mariana De; Sequeira, Mariana; Bizarra-Rebelo, Tiago; Bento, Fábio; Dejung, Mario; Narciso, Marta Valido; López-Escobar, Lara; Ferreira, João; Butter, Falk; Bringaud, Frédéric; Gjini, Erida; Figueiredo, Luísa M.

doi:10.1038/s41467-022-34622-w

Cited by 17 publications

(16 citation statements)

References 44 publications

(57 reference statements)

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“…Altogether, our results outline a model in which T. brucei parasites “hide” in extravascular spaces to generate new antigenic variants capable of exiting tissues and aiding in systemic immune evasion. Coupled with other recent studies 9–13,35 , this suggests a new framework for the progression and pathogenesis of T. brucei infections. Instead of being the primary parasite reservoir, the blood may represent a transient population that is regularly re-seeded by extravascular parasites.…”

Section: Discussionsupporting

confidence: 69%

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: Discussionsupporting

confidence: 69%

Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

Beaver

Crilly

Hakim

et al. 2022

Preprint

Self Cite

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“…Characterised extravascular locations for trypanosomes include the skin, lungs and adipose tissue (Capewell et al, 2016;Mabille et al, 2022;Trindade et al, 2016), and the migration between the adipose tissues and blood has recently been estimated to be 11% of blood parasites/per milligram of tissue/day, highlighting that there is significant, though restricted, potential for exchange (Trindade et al, 2022). These extravascular compartments have recently been identified as sites of elevated antigenic diversity (Beaver et al, 2023) and, if this is combined with enhanced replicative capacity, could seed parasites into the bloodstream where they rapidly arrest and transition to stumpy forms.…”

Section: Discussionmentioning

confidence: 99%

When is a slender not a slender? The cell-cycle arrest and scarcity of slender parasites challenges the role of bloodstream trypanosomes in infection maintenance

Larcombe

Briggs

Savill

et al. 2023

Preprint

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The development of Trypanosoma brucei in its mammalian host is marked by a distinct morphological change as replicative 'slender' forms differentiate into cell-cycle arrested 'stumpy' forms in a quorum-sensing dependent manner. Although stumpy forms dominate chronic infections at the population level, the proportion of replicative parasites at the individual cell level and the irreversibility of arrest in the bloodstream is unclear. Here, we experimentally demonstrate that developmental cell cycle arrest is definitively irreversible in acute and chronic infections in mice. Furthermore, analysis of replicative capacity and single-cell transcriptome profiling reveals a temporal hierarchy, whereby cell-cycle arrest and appearance of a stumpy-like transcriptome precedes irreversible commitment and morphological change. Unexpectedly, we show that proliferating parasites are exceptionally scarce in the blood after infections are established. This challenges the ability of bloodstream trypanosomes to sustain infection by proliferation or antigenic variation, these parasites instead being overwhelmingly adapted for transmission.

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“…These sites are believed to be immune privileged, possibly providing a safe haven for parasitic cells [123]. However, there are emerging reports of trypanosomes accumulating in adipose tissue, whereby they trigger an immune response [124]. The immune response leads to adipocyte lysis (adipolysis) [124].…”

Section: Physiological Challenges To Effective Drug Deliverymentioning

confidence: 99%

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

Jamabo,

Mahlalela,

Edkins

et al. 2023

IJMS

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Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite Trypanosoma brucei, and targeted for eradication by 2030. The COVID-19 pandemic contributed to the lengthening of the proposed time frame for eliminating human African trypanosomiasis as control programs were interrupted. Armed with extensive antigenic variation and the depletion of the B cell population during an infectious cycle, attempts to develop a vaccine have remained unachievable. With the absence of a vaccine, control of the disease has relied heavily on intensive screening measures and the use of drugs. The chemotherapeutics previously available for disease management were plagued by issues such as toxicity, resistance, and difficulty in administration. The approval of the latest and first oral drug, fexinidazole, is a major chemotherapeutic achievement for the treatment of human African trypanosomiasis in the past few decades. Timely and accurate diagnosis is essential for effective treatment, while poor compliance and resistance remain outstanding challenges. Drug discovery is on-going, and herein we review the recent advances in anti-trypanosomal drug discovery, including novel potential drug targets. The numerous challenges associated with disease eradication will also be addressed.

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Slow growing behavior in African trypanosomes during adipose tissue colonization

Cited by 17 publications

References 44 publications

Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

When is a slender not a slender? The cell-cycle arrest and scarcity of slender parasites challenges the role of bloodstream trypanosomes in infection maintenance

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

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