Organotypic endothelial adhesion molecules are key for<i>Trypanosoma brucei</i>tropism and virulence

Niz, Mariana De; Bras,; Pedro, Mafalda; Nascimento,; Franco, Cláudio A.; Figueiredo, Luísa M.

doi:10.1101/2021.02.26.433042

Cited by 3 publications

References 79 publications

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Adipocyte lipolysis protects the host againstTrypanosoma bruceiinfection

Machado

Hofer

Zechner

et al. 2022

Preprint

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Trypanosoma brucei, an etiological agent of African trypanosomiasis, colonizes the interstitial spaces of the adipose tissue in disproportionately high numbers, inducing a robust local immune response. Loss of body weight, including loss of adipose mass, is a hallmark symptom of African trypanosomiasis. Nevertheless, it is unclear which molecular mechanisms drive this loss of adipose mass and in turn whether it contributes to pathology. Here we show that lipolysis is activated early in infection in adipose tissue of T. brucei-infected mice. This activation is dependent on immune activation, as mice deficient for both B and T lymphocytes failed to upregulated adipocyte lipolysis upon infection and retained higher fat mass. Genetic ablation of the rate limiting adipose triglyceride lipase specifically from adipocytes in mice (AdipoqCre/+-Atglfl/fl) prevented the upregulation of adipocyte lipolysis during infection, leading to reduced loss of fat mass and adipocyte volume. Surprisingly infected AdipoqCre/+-Atglfl/flmice succumbed earlier to infection and presented a higher parasite burden in the gonadal adipose tissue, indicating that lipolysis limits the growth of the parasite population. Collectively, this work provides molecular mechanistic insight into the loss of fat mass in African trypanosomiasis and identifies adipocyte lipolysis as a host-protective mechanism during a T. brucei infection.

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Adipocyte lipolysis protects the host againstTrypanosoma bruceiinfection

Machado

Hofer

Zechner

et al. 2022

Preprint

Self Cite

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A murine model ofTrypanosoma brucei-induced myocarditis and cardiac dysfunction

Crilly,

Zita,

Beaver

et al. 2023

Preprint

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Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases (HAT and AAT). Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models of T. brucei infection. However, despite the importance of T. brucei as a cause of cardiac dysfunction and the dramatic socioeconomic impact of African trypanosomiases in sub-Saharan Africa, there are currently no reproducible murine models of T. brucei-associated cardiomyopathy. We present the first clinically relevant, reproducible murine model of cardiac dysfunction in chronic T. brucei infection. Similar to humans, mice showed histological evidence of myocarditis and elevation of serum NT-proBNP. Serum NT-proBNP levels were elevated prior to the development of severe ventricular dysfunction. On flow cytometry, myocarditis was associated with an increase of most myocardial immune cell populations, including multiple T cell and macrophage subsets, corroborating the notion that T. brucei-associated cardiac damage is an immune-mediated event. This novel mouse model represents a powerful and practical tool to investigate the pathogenesis of T. brucei-mediated heart damage and support the development of therapeutic options for T. brucei-associated cardiac disease.

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The lymphatic system favours survival of a unique T. brucei population

Machado,

Temudo,

Niz

2023

Biology Open

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Trypanosoma brucei colonize and multiply in the blood vasculature, as well as in various organs of the host's body. Lymph nodes have been previously shown to harbour large numbers of parasites, and the lymphatic system has been proposed as a key site that allows T. brucei distribution through, and colonization of the mammalian body. However, visualization of host-pathogen interactions in the lymphatic system has never captured dynamic events with high spatial and temporal resolution throughout infection. In our work, we used a mixture of tools including intravital microscopy and ex vivo imaging to study T. brucei distribution in 20 sets of lymph nodes. We demonstrate that lymph node colonization by T. brucei is different across lymph node sets, with the most heavily colonized being the draining lymph nodes of main tissue reservoirs: the gonadal white adipose tissue and pancreas. Moreover, we show that the lymphatic vasculature is a pivotal site for parasite dispersal, and altering this colonization by blocking LYVE-1 is detrimental for parasite survival. Additionally, parasites within the lymphatic vasculature have unique morphological and behavioural characteristics, different to those found in the blood, demonstrating that across both types of vasculature, these environments are physically separated. Finally, we demonstrate that the lymph nodes and the lymphatic vasculature undergo significant alterations during T. brucei infection, resulting in oedema throughout the host's body.

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Organotypic endothelial adhesion molecules are key forTrypanosoma bruceitropism and virulence

Cited by 3 publications

References 79 publications

Adipocyte lipolysis protects the host againstTrypanosoma bruceiinfection

Adipocyte lipolysis protects the host againstTrypanosoma bruceiinfection

A murine model ofTrypanosoma brucei-induced myocarditis and cardiac dysfunction

The lymphatic system favours survival of a unique T. brucei population

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