Metabolic Profiling of Central Nervous System Disease in Trypanosoma brucei rhodesiense Infection

Lamour, Sabrina; Alibu, Vincent P.; Holmes, Elaine; Sternberg, Jeremy M.

doi:10.1093/infdis/jix466

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…Even so—and similarly to proteomics—the most significant changes in metabolite abundances between HAT stages were observed in the CSF, indicating that finding a blood (or urine) staging tool with the appropriate specificity and sensitivity remains a difficult task. Different results have very recently been published on T. b. rhodesiense CSF samples using 1 H NMR spectroscopy . No CSF metabolic marker was able to differentiate between stages, however, altered levels of specific metabolic features (including 3‐hydroxybutyrate, alanine, mannose, and urea) were reported to be indicative of the presence of neurological signs, independently from the disease stage, and to correlate with neuro‐inflammation.…”

Section: Omics and Hat Biomarkersmentioning

confidence: 91%

Sleeping Sickness in the ‘Omics Era

Tiberti

Sanchez

2018

Proteomics Clinical Apps

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Sleeping sickness is a neglected tropical disease caused by Trypanosoma brucei parasites, affecting the poorest communities in sub-Saharan Africa. The great efforts done by the scientific community, local governments, and non-governmental organizations (NGOs) via active patients' screening, vector control, and introduction of improved treatment regimens have significantly contributed to the reduction of human African trypanosomiasis (HAT) incidence during the last 15 years. Consequently, the WHO has announced the objective of HAT elimination as a public health problem by 2020. Studies at both parasite and host levels have improved our understanding of the parasite biology and the mechanisms of parasite interaction with its mammalian host. In this review, the impact that 'omics studies have had on sleeping sickness by revealing novel properties of parasite's subcellular organelles are summarized, by highlighting changes induced in the host during the infection and by proposing potential disease markers and therapeutic targets.

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Section: Omics and Hat Biomarkersmentioning

confidence: 91%

Sleeping Sickness in the ‘Omics Era

Tiberti

Sanchez

2018

Proteomics Clinical Apps

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“…In murine models, trypanosome infection is associated with global host metabolic disturbances, including in the bloodstream, but also in other anatomical locations such as the gut and brain [ 170 , 181 , 182 ]. These changes are the result of both host and parasite metabolism.…”

Section: Parasite Metabolism and Virulencementioning

confidence: 99%

Pathogenicity and virulence of African trypanosomes: From laboratory models to clinically relevant hosts

et al. 2023

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African trypanosomes are vector-borne protozoa, which cause significant human and animal disease across sub-Saharan Africa, and animal disease across Asia and South America. In humans, infection is caused by variants of Trypanosoma brucei , and is characterized by varying rate of progression to neurological disease, caused by parasites exiting the vasculature and entering the brain. Animal disease is caused by multiple species of trypanosome, primarily T. congolense , T. vivax, and T. brucei . These trypanosomes also infect multiple species of mammalian host, and this complexity of trypanosome and host diversity is reflected in the spectrum of severity of disease in animal trypanosomiasis, ranging from hyperacute infections associated with mortality to long-term chronic infections, and is also a main reason why designing interventions for animal trypanosomiasis is so challenging. In this review, we will provide an overview of the current understanding of trypanosome determinants of infection progression and severity, covering laboratory models of disease, as well as human and livestock disease. We will also highlight gaps in knowledge and capabilities, which represent opportunities to both further our fundamental understanding of how trypanosomes cause disease, as well as facilitating the development of the novel interventions that are so badly needed to reduce the burden of disease caused by these important pathogens.

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“…Here we have applied these light-sheets for rapid high-resolution mesoscale imaging and quantification of neuroinflammation during T. brucei infection using an experimental murine model of infection that faithfully recapitulates the severe neuroinflammatory state observed in patients infected with T. b. rhodesiense (Rodgers et al, 2015(Rodgers et al, , 2019aLamour et al, 2017) observed a significant increase in the labelling intensity of the protein glia fibrillary acidic protein (GFAP) (Yang and Wang, 2015), used here as a proxy for astrocyte reactivity and inflammation, around the circumventricular organs (CVOs), coinciding with the proposed sites of entry of the parasites into the CNS (Bentivoglio et al, 2018). Concomitantly, GFAP positive cells (typically astrocytes and ependymocytes) located in the vicinity of the ventricular structures display a greater number of cytoplasmatic processes when compared to either parenchymal astrocytes in the infected brain, or those found in naïve controls.…”

Section: Introductionmentioning

confidence: 99%

Application of light-sheet mesoscopy to image host-pathogen interactions in intact organs

Battistella

Quintana

McConnell

2022

Preprint

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Human African Trypanosomiasis (HAT) is a disease caused by the extracellular parasite Trypanosoma brucei that affects the central nervous system (CNS) during the chronic stage of the infection, inducing neuroinflammation, coma, and death if left untreated. However, little is known about the structural change happening in the brain as result of the infection. So far, infection-induced neuroinflammation has been observed with conventional methods, such as immunohistochemistry, electron microscopy, and 2-photon microscopy only in small portions of the brain, which may not be representative of the disease. In this paper, we have used a newly-developed light-sheet illuminator to image the level of neuroinflammation in chronically infected mice and we use analyse these data to compare the infection in na&iumlve controls. This system was developed for imaging in combination with the Mesolens objective lens, providing sub-cellular resolution for imaging volumes exceeding 39 mm3 in an acquisition time of only 8 hours. The mouse brain specimens were cleared using CUBIC+, followed by antibody staining to locate Glial Fibrillary Acid Protein (GFAP) expressing cells, primarily astrocytes and ependymocytes, used here as a proxy for cell reactivity and gliosis. The large capture volume allowed us to detect GFAP+ cells and spatially resolve the innate responses to T. brucei infection. Based on morphometric analyses and spatial distribution of GFAP+ cells, our data demonstrates a significant increase in cell dendrite branching around the lateral ventricle, as well as dorsal and ventral third ventricles, that are negatively correlated with the branch extension in distal sites from the circumventricular spaces. To our knowledge, this is the first report highlighting the potential of light sheet mesoscopy to characterise the inflammatory responses of the mouse brain to parasitic infection at the cellular level in intact cleared organs, opening new avenues for the development of new mesoscale imaging techniques for the study of host-pathogen interactions.

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Metabolic Profiling of Central Nervous System Disease in Trypanosoma brucei rhodesiense Infection

Cited by 9 publications

References 33 publications

Sleeping Sickness in the ‘Omics Era

Sleeping Sickness in the ‘Omics Era

Pathogenicity and virulence of African trypanosomes: From laboratory models to clinically relevant hosts

Application of light-sheet mesoscopy to image host-pathogen interactions in intact organs

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