Host triacylglycerols shape the lipidome of intracellular trypanosomes and modulate their growth

Abstract

Intracellular infection and multi-organ colonization by the protozoan parasite, Trypanosoma cruzi, underlie the complex etiology of human Chagas disease. While T. cruzi can establish cytosolic residence in a broad range of mammalian cell types, the molecular mechanisms governing this process remain poorly understood. Despite the anticipated capacity for fatty acid synthesis in this parasite, recent observations suggest that intracellular T. cruzi amastigotes may rely on host fatty acid metabolism to support infection. To investigate this prediction, it was necessary to establish baseline lipidome information for the mammalian-infective stages of T. cruzi and their mammalian host cells. An unbiased, quantitative mass spectrometric analysis of lipid fractions was performed with the identification of 1079 lipids within 30 classes. From these profiles we deduced that T. cruzi amastigotes maintain an overall lipid identity that is distinguishable from mammalian host cells. A deeper analysis of the fatty acid moiety distributions within each lipid subclass facilitated the high confidence assignment of host- and parasite-like lipid signatures. This analysis unexpectedly revealed a strong host lipid signature in the parasite lipidome, most notably within its glycerolipid fraction. The near complete overlap of fatty acid moiety distributions observed for host and parasite triacylglycerols suggested that T. cruzi amastigotes acquired a significant portion of their lipidome from host triacylglycerol pools. Metabolic tracer studies confirmed long-chain fatty acid scavenging by intracellular T. cruzi amastigotes, a capacity that was significantly diminished in host cells deficient for de novo triacylglycerol synthesis via the diacylglycerol acyltransferases (DGAT1/2). Reduced T. cruzi amastigote proliferation in DGAT1/2-deficient fibroblasts further underscored the importance of parasite coupling to host triacylglycerol pools during the intracellular infection cycle. Thus, our comprehensive lipidomic dataset provides a substantially enhanced view of T. cruzi infection biology highlighting the interplay between host and parasite lipid metabolism with potential bearing on future therapeutic intervention strategies.

The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids

“…In fact, the intracellular environment is poor in glucose and amastigotes are unable to take this sugar up from an environment at concentrations below the millimolar range [ 281 ], despite the fact that amastigotes can take up and metabolize glucose when available at high concentrations [ 282 ]. It was also demonstrated that amastigotes can acquire fatty acids from the host to support infection [ 283 , 284 ].…”

Aging induces Nlrp3 inflammasome dependent adipose B cell expansion to impair metabolic homeostasis

“…In the young, the adipose tertiary lymphoid structures are local sites of immune surveillance, contributing to the clearance of TLR agonists and pathogens (Benezech et al, 2015; Jackson-Jones et al, 2016; Moro et al, 2010); however, our data suggest that FALCs also control metabolic capacity of adipose tissue. Lipolysis is critical in infections and specific metabolic substrates help drive an efficient and effective immune response (Gazos-Lopes et al, 2017; Wang et al, 2018). Whether B cells regulate host energy homeostasis during various pathophysiological situations requiring metabolic substrates remains to be determined.…”

A novel mechanosensitive channel controls osmoregulation, differentiation and infectivity inTrypanosoma cruzi

“…cruzi regulates the size of the population. Recent studies show that intracellular amastigotes regulate their growth and metabolism in response to the host conditions (66,67). MSCs channels are regulators of homeocrowding, a mechanism that allows bacteria to maintain a constant level of macromolecular excluded volume at the expense of accumulating or releasing small osmolytes and metabolites (68,69).…”