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Impact of adipose tissue colonization by Trypanosoma brucei during infection
Publication . Machado, Henrique; Figueiredo, Luísa Miranda
African trypanosomiasis is an infectious disease caused by unicellular and extracellular parasites of the Trypanosomatidae family, including Trypanosoma brucei. Both Human and animal African trypanosomiasis are characterized by a pronounced loss of fat and skeletal muscle mass. T. brucei occupies both intravascular and extravascular compartments of the mammalian host. In the mouse model of infection, T. brucei colonizes the adipose tissue in disproportionately high numbers when compared with most other organs. The properties of the adipose tissue microenvironment, immunological and others, which enable such extensive colonization, are still incompletely understood. Moreover, the impact of adipose tissue colonization on the loss of fat mass observed during natural infections, and the impact of fat mass loss itself on disease pathology are unknown. Here, we show that during infection the adipose tissue acquires a marked transcriptomic immune signature. This correlated with the accumulation of both innate and adaptive immune cells consistent with a T helper (Th) 1 response. Moreover, as observed for the serum, we found increasingly higher titers of IgM and IgG specific for the parasite’s surface variant glycoprotein in the adipose tissue’s interstitial fluid. Similar to the blood, parasite clearance from the adipose tissue was dependent on T and B cells and the hallmark Th1 cytokine interferon gamma. Interestingly, while the complement system was dispensable to eliminate circulating parasites, mice lacking the complement component 3 showed reduced elimination of parasites from the adipose tissue. This suggests that the complement system may play an important role in the clearance of highly parasitized extravascular compartments.
In addition to studying the immunological surveillance of the adipose tissue, we also studied how adipocyte metabolism is modulated by a T. brucei infection. Here, we show that during infection, white adipose tissue depots progressively reduce in size and that this reduction correlates with loss of adipocyte lipid droplet volume (i.e. fat containing organelle). In turn, this loss of adipose tissue weight is preceded by an increase in ex vivo adipocyte lipolysis. This increase in lipolysis proved to be central in loss of fat mass, as adipocyte-specific adipose tissue triglyceride lipase deficient (AdipoqCre/+-Atglfl/fl) mice, which have reduced lipolysis, were more resistant to loss of total fat mass and kept higher adipocyte lipid droplet volumes than wild-type (WT) littermate controls (Atglfl/fl). Moreover, adipocyte lipolysis showed host-protective effects, as AdipoqCre/+- Atglfl/fl mice succumbed earlier to infection than Atglfl/fl controls. In addition to increased survival, our data suggest that increased lipolysis improves local parasite burden control. On one hand, AdipoqCre/+-Atglfl/fl mice present transiently higher adipose tissue parasite burdens than Atglfl/fl controls. On the other hand, chemical induction of adipocyte lipolysis in an in vitro adipocyte-T. brucei co-culture system significantly reduces parasite growth. Lastly, we shed light on the upstream signals that induce adipocyte lipolysis. Here, we found that T. brucei promotes lipolysis in in vitro grown co-cultured adipocytes. In addition to parasite cues, we found that T and B cells are central in the induction of fat mass loss and that serum factor produce by these cells are able to induce adipocyte lipolysis. Overall, in this work we show that during a T. brucei infection a trypanocydal immune response is mounted in the adipose tissue and that as infection progresses a loss of fat mass occurs through host-protective ATGL-dependent adipocyte lipolysis
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Fundação para a Ciência e a Tecnologia
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OE
Número da atribuição
PD/BD/128286/2017