Mediated by Host Cell-Derived Microvesicles Immune Evasion Trypanosoma cruzi

The innate immune system is the first mechanism of vertebrate defense against pathogen infection. In this study, we present evidence for a novel immune evasion mechanism of Trypanosoma cruzi, mediated by host cell plasma membrane-derived vesicles. We found that T. cruzi metacyclic trypomastigotes induced microvesicle release from blood cells early in infection. Upon their release, microvesicles formed a complex on the T. cruzi surface with the complement C3 convertase, leading to its stabilization and inhibition, and ultimately resulting in increased parasite survival. Furthermore, we found that TGF-b–bearing microvesicles released from monocytes and lymphocytes promoted rapid cell invasion by T. cruzi, which also contributed to parasites escaping the complement attack. In addition, in vivo infection with T. cruzi showed a rapid increase of microvesicle levels in mouse plasma, and infection with exogenous microvesicles resulted in increased T. cruzi parasitemia. Altogether, these data support a role for microvesicles contributing to T. cruzi evasion of innate immunity. T rypanosoma cruzi, the causative agent of Chagas disease, has evolved several mechanisms to survive the hostile environments encountered during its life cycle (1). The T. cruzi life cycle alternates between an insect vector and a vertebrate host (1). In the insect, T. cruzi multiplies as epimastigotes that differentiate to metacyclic trypomastigotes (vertebrate infec-tive stage), which are released on the host skin during transmission by the insect bite. This parasite has to evade the innate immune system and infect host cells to progress in the life cycle. Inside the cells, T. cruzi differentiates to amastigotes (multiplicative intra-cellular stage), which after several rounds of division differentiate to bloodstream trypomastigotes. The latter disrupt the cells and circulate in the blood, infecting other cells or being taken by the insect vector, thereby restarting the life cycle. One of the main barriers encountered during infection of vertebrates is the complement system (2). The complement system is a protein cascade activated upon pathogen recognition and culminating in pathogen lysis (2). It can be activated by classical, lectin, or alternative pathways, as follows. The classical pathway is activated when IgG/IgM bind to the pathogen and associate with the C1 complex (C1q-r 2 s 2), which cleaves components C2 and C4 and generates C3 convertase (C4b2a). The lectin pathway is activated when mannan-binding lectin (MBL), L-ficolin, and/or H-ficolin recognize pathogen carbohydrates. They associate with MBL-associated serine protease-2 (MASP-2), which cleaves C2 and C4 to form C3 convertase (C4b2a). The alternative pathway is initiated …