Trypanosoma cruzi Infection and Host Lipid Metabolism

Figure 1

Trypanosoma cruzi interacting with various components of host lipid metabolism. (a) T. cruzi infects macrophage and activates TLR-2 signaling which causes the increased lipid bodies (LB) number and altered LB morphology. This effect is further enhanced by macrophage uptake of apoptotic cells. Increased LB number causes increased eicosanoid production, which leads to upregulation of TGF- and increased cell susceptibility to T. cruzi infection. (b) T. cruzi uses adipocytes as a reservoir for chronic infection. T. cruzi infection causes adipocytes to display an inflammatory phenotype, upregulating cytokines such as IL-1, IFN-, TNF-, CCL2, CXCL10, and CCL5. TLR-2 and 9, which are essential to T. cruzi infection, are also upregulated. The infection also causes downregulation of adiponectin secretion via PPAR- expression. (c) Host LDL inhibits T. cruzi trans-sialidase and increases T. cruzi infection in vitro. LDL can be taken up by the liver and extrahepatic cells by LDLR. It is unknown whether LDL-LDLR interaction plays a role in T. cruzi infection. (d) T. cruzi enters host cell via LDLR. LDL-R activation leads to lysosomal recruitment to parasitophorous vacuole and parasite internalization. (e) HDL inhibits T. cruzi trans-sialidase activity and increases T. cruzi infection in vitro. HDL is uptaken by host cells via receptor mediated interaction with SR-BI. Whether this interaction can be utilized by T. cruzi cell entry process is not known. (f) Apo A-I in the HDL complex is cleaved by the major cysteine protease of T. cruzi, cruzipain. Cruzipain and trans-sialidase are similarly expressed and located during different life stages of T. cruzi. It is possible that HDL is bound to the surface of T. cruzi trypomastigotes by trans-sialidase and is cleaved by cruzipain in the acidic environment in the parasitophorous vacuole. Host cholesterol transport by VLDL, LDL, and HDL is indicated in red arrows. Host VLDL and lipid-poor nascent HDL particles are produced in the liver. By effluxing cholesterol, host VLDL transforms to become LDL and nascent HDL becomes mature HDL. LDL particles can be oxidized and uptaken by macrophage. Lipid-laden macrophages are termed foam cells and are major contributors in host atherosclerosis development. HDL effluxes cholesterol from peripheral tissue via the action of ABCA1 or ABCG1 and returns cholesterol to hepatic tissues for storage or excretion.