Adipocyte lipolysis protects the host against<i>Trypanosoma brucei</i>infection

Machado, Henrique; Hofer, Peter; Zechner, Rudolf; Figueiredo, Luísa M.

doi:10.1101/2022.11.05.515274

Cited by 8 publications

(6 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PCF parasites respond by scavenging large amount FA sources from the serum, if in high-fat media, or by reducing the ratio of C22/C20 PUFAs, if in low-fat media, to maintain the membrane homeostasis and rescue their growth. We also found that, in keeping with recent studies by Machado et al, (39) some environmental PUFAs, can have a detrimental effect on the parasite cell growth, like shown for WT and Δ6-KD PCF under DHA supplementation. Despite that, WT and Δ6-KD PCF cells showed the typical full range of cellular FA species, where an increase of C18:0/C18:1 and C18:2 ratio was observed to ensure once again membrane homeostasis and cell survival.…”

Section: Discussionsupporting

confidence: 92%

Exploring the activity and the essentiality of the putative Δ6-desaturase in the procyclic and bloodstream forms ofTrypanosoma brucei

Cerone,

Smith

2023

Preprint

View full text Add to dashboard Cite

Trypanosomatids have been shown to possess an exclusive and finely regulated biosynthetic pathway forde novosynthesis of fatty acids (FAs) and particularly of polyunsaturated fatty acids (PUFAs). The key enzymes for the process of unsaturation are known as desaturases. In this work, we explored the biocatalytic activity of the putative Δ6-desaturase (Tb11.v5.0580) in the native organismT. brucei. Utilising fatty acid analysisviaGC-MS, we were able to elucidateviagenetic manipulation of the level of expression of Δ6-desaturases in both procyclic (PCF) and bloodstream (BSF) forms ofT. bruceiandviasupplementation of the media with various levels of FA sources, that docosahexaenoic acid (22:6) and/or docosapentaenoic acid (22:5), and arachidonic acid (20:4) and/or docosatetraenoic acid (22:4) are the products and the substrates respectively of this Δ6-desaturases. Interestingly, we were able to observe,vialipidomic analysis with ESI-MS/MS, an increase in inositol-phosphoryl ceramide (IPC) in response to the overexpression of Δ6-desaturases in low-fat media, both in PCF and rather surprisingly in BSF. The formation of IPC is normally only observed in the stumpy and procyclic forms ofT. brucei. Therefore, the expression levels of Δ6-desaturases, which varies between BSF and PCF, might be involved in the cascade(s) of metabolic events that cause these remodelling of the lipid pools and ultimately morphological changes, which are key to the transition between these life-cycle stages.Author summaryTrypanosoma bruceiis a unicellular parasite that causes human and animal African trypanosomiasis. These parasites have the special ability to make their own pool of fat molecules by assembling and modifying the fatty acid building blocks that they take up from the human and animal hosts and from the insect vector. In this study, we investigated the unknown activity of a desaturase enzyme. By modulating its activity, we showed that it can make different levels of high-value long chain polyunsaturated fatty acids (LC-PUFAs) often known as omega-6 and omega-3. If we increase or reduce the fat sources available from the outer environment, the cells respond by making more or less LC-PUFAs and by forming different type of lipids and sphingolipids for their cellular membranes. We highlighted that by tuning the level of activity of the desaturase and varying the type and amounts of fat sources available to the cells,T. bruceican alter their morphology. This is key for the parasites to adapt to the various environments and the nutrients therein that are often constantly changing within the host, allowing the shift between different life-stages during the complex life cycle from the insect vector to the host and back.

show abstract

Section: Discussionsupporting

confidence: 92%

Exploring the activity and the essentiality of the putative Δ6-desaturase in the procyclic and bloodstream forms ofTrypanosoma brucei

Cerone,

Smith

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus, we propose a model whereby subcutaneous adipocytes (in addition to Langerhans cells and keratinocytes) have a critical role as coordinators of local innate and adaptive immune responses. In the context of trypanosome infection, subcutaneous adipocytes may detect the presence of parasites (e.g., via Toll-like receptor signalling) to trigger the recruitment and activation of innate immune cells such as gd T cells to mobilise energy stores to meet the energetic requirements needed to control infection, as recently proposed 59 .…”

Section: Discussionmentioning

confidence: 99%

Spatially-resolved single cell transcriptomics reveal a critical role for γδ T cells in the control of skin inflammation and subcutaneous adipose wasting during chronic Trypanosoma brucei infection

Quintana

Sinton

Chandrasegaran

et al. 2023

Preprint

View full text Add to dashboard Cite

African trypanosome parasites colonise the skin in a process important for parasite transmission. However, how the skin responses to trypanosome infection remain unresolved. Here, using a combination of spatial and single cell transcriptomics, coupled with in vivo genetic models, we investigated the local immune response of the skin in a murine model of infection. First, we detected a significant expansion of IL-17A-producing γδT cells (primarily Vγ6+) in the infected murine skin compared to naïve controls that occur mainly in the subcutaneous adipose tissue. Second, interstitial preadipocytes located in the subcutaneous adipose tissue upregulate several genes involved in inflammation and antigen presentation, including T cell activation and survival. In silico cell-cell communication suggests that adipocytes trigger γδ T cell activation locally via Cd40, Il6, Il10, and Tnfsf18 signalling, amongst others. Third, mice deficient in IL-17A-producing γδ T cells show extensive inflammation, increased frequency of skin-resident IFNγ-producing CD8+ T cells and limited subcutaneous adipose tissue wasting compared to wild-type infected controls, independent of TH1 CD4+ T cells and parasite burden. Based on these observations, we proposed a model whereby adipocytes as well as Vγ6+ cells act concertedly in the subcutaneous adipose tissue to limit skin inflammation and tissue wasting. These studies shed light onto the mechanisms of γδ T cell-mediated immunity in the skin in the context of African trypanosome infection, as well as a potential role of immature and mature adipocytes as homeostatic regulators in the skin during chronic infection.

show abstract

“…Finally, in response to our third question, we found that both, lymph nodes and the lymphatic vasculature are highly remodeled throughout infection. While we have shown that remodeling of equivalent nature occurs in other organs (De Niz et al, 2021;Machado et al, 2022;Trindade et al, 2016), it is important to consider the implications of lymphatic system compromise. Although T. brucei is not considered per se a lymphatic disease as lymphatic filariasis is, it induces remarkable changes in systemic homeostasis as shown by the presence of major oedema (composed of heavily parasitized fluid) throughout the whole mouse body.…”

Section: Discussionmentioning

confidence: 96%

The lymphatic system favours survival of a uniqueT. bruceipopulation, and its invasion results in major host pathology

Machado

Niz

2023

Preprint

Self Cite

View full text Add to dashboard Cite

Trypanosoma brucei colonise 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 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 a physical separation of environments across both types of vasculature. Finally, we demonstrate that the lymph nodes and the lymphatic vasculature undergo significant alterations during T. brucei infection, resulting in major oedema throughout the host's body.

show abstract

Adipocyte lipolysis protects the host againstTrypanosoma bruceiinfection

Cited by 8 publications

References 48 publications

Exploring the activity and the essentiality of the putative Δ6-desaturase in the procyclic and bloodstream forms ofTrypanosoma brucei

Exploring the activity and the essentiality of the putative Δ6-desaturase in the procyclic and bloodstream forms ofTrypanosoma brucei

Spatially-resolved single cell transcriptomics reveal a critical role for γδ T cells in the control of skin inflammation and subcutaneous adipose wasting during chronic Trypanosoma brucei infection

The lymphatic system favours survival of a uniqueT. bruceipopulation, and its invasion results in major host pathology

Contact Info

Product

Resources

About