Arginase in Trypanosoma cruzi infection: macrophage receptors, cellular interactions and intracellular signals.

FABIO CERBAN, CINTHIA STEMPIN, LAURA DULGERIAN, VANINA GARRIDO.

Conferencia; IV Simposium de Inmunoparasitologia; 2010

Parasites have elaborated a variety of strategies to escape of the immune response and to make possible their survival and replication in the host. Some parasites modulate the production of several toxic molecules such as nitric oxide (ON). ON is produced in macrophages (Mo) after stimulation with microbial products or cytokines. In contrast, alternatively activated Mo (AAMo) fail to produce ON due to the arginase induction and consequently they have diminished their capacity to kill intracellular pathogens. Our group has demonstrated that cruzipain (Cz), a T. cruzi antigen, modulates the immune response against T. cruzi through the induction of arginase but not iNOS in Mo. In addition, Cz induces p38 MAPKinase phosphorylation that regulate arginase/iNOS activation favoring T. cruzi growth. To study the role of C-type lectin-like receptors in this phenomenon, we investigate the mannose receptor (MR) since it binds to microbial structures bearing mannose, fucose and N-acetylglucosamine on their surface. Besides, MR is expressed in AAMo and Cz has a domain highly mannosylated. Consequently, our results suggest that mannosylated bovine serum albumin (manBSA, the MR specific ligand) and Cz might interact with the same receptor (MR). Moreover, we show that pre-incubation with manBSA as well as Cz increase MR recycling on Mo surface and shift the iNOS/arginase balance to arginase. Moreover, MR blockade on Mo showed a reduction in parasite growth. Thus MR recycling also favors T. cruzi replication. Finally, to investigate additional interactions that regulate arginase, we study the role of programmed death 1 (PD-1) and its ligands (PD-L1 and PD-L2) in T. cruzi infection since these molecules are involved in immunosuppression and immune escape mechanisms in viral infections. We study the role of these molecules using PD-L2 KO mice and demonstrate that PD-L2 regulates arginase induction and modifies T. cruzi survival in Mo during murine experimental infection.