Regulation and use of the extracellular matrix by Trypanosoma cruzi during early infection

Abstract

Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global becoming a new worldwide challenge. For more than a century since its discovery, it has remained neglected with no effective drugs or vaccines. The mechanisms by which Trypanosoma cruzi regulates and uses the extracellular matrix (ECM) to invade cells and cause disease are just beginning to be understood. Here we critically review and discuss the regulation of the ECM interactome by T. cruzi, the use of the ECM by T. cruzi and analyze the molecular ECM/T. cruzi interphase during the early process of infection. It has been shown that invasive trypomastigote forms of T. cruzi use and modulate components of the ECM during the initial process of infection. Infective trypomastigotes up-regulate the expression of laminin γ-1 (LAMC1) and thrombospondin (THBS1) to facilitate the recruitment of trypomastigotes to enhance cellular infection. Silencing the expression of LAMC1 and THBS1 by stable RNAi dramatically reduces trypanosome infection. T. cruzi gp83, a ligand that mediates the attachment of trypanosomes to cells to initiate infection, up-regulates LAMC1 expression to enhance cellular infection. Infective trypomastigotes use Tc85 to interact with laminin, p45 mucin to interact with LAMC1 through galectin-3 (LGALS3), a human lectin, and calreticulin (TcCRT) to interact with TSB1 to enhance cellular infection. Silencing the expression of LGALS3 also reduces cellular infection. Despite the role of the ECM in T. cruzi infection, almost nothing is known about the ECM interactome networks operating in the process of T. cruzi infection and its ligands. Here, we present the first elucidation of the human ECM interactome network regulated by T. cruzi and its gp83 ligand that facilitates cellular infection. The elucidation of the human ECM interactome regulated by T. cruzi and the dissection of the molecular ECM/T. cruzi interphase using systems biology approaches are not only critically important for the understanding of the molecular pathogenesis of T. cruzi infection but also for developing novel approaches of intervention in Chagas disease.

Mechanisms of cellular invasion by intracellular parasites

“…Parasite binding of extracellular matrix proteins (ECM) (fibronectin, laminin and collagen) and proteoglycans (heparin, heparin sulfate) is also implicated in invasion[121–124]. The gp85/TS superfamily of proteins been shown to bind multiple ECM components[123].…”

Interação parasita-célula hospedeira: modificação de proteínas de Tripanosoma cruzi durante adesão à matriz extracelular

“…genes codificam proteínas que apresentam o motivo VTxNVxLYNR, conservado (Freitas, et al, 2011), incluindo toda as proteínas do grupo II, que engloba as glicoproteínas de membrana com capacidade de ligação a elementos da matriz extracelular (Marroquin-Quelopana, et al, 2004, Nde, et al, 2012 e a elementos do citoesqueleto da célula hospedeira (Magdesian, et al, 2001), como Tc85-11, uma proteína recombinante da Tc85.…”

“…Outros membros da família, de diferentes massas moleculares, como gp83 (Villalta, et al, 2009) foram implicados na invasão, inclusive com capacidade de se ligar a laminina e a outros elementos da ECM (revisto em Nde, et al, 2012), reforçando ainda mais a importância dessa superfamília gênica e da ligação entre ECM e o parasita para a ativação de vias responsáveis pela capacidade invasiva de T. cruzi.…”

“…Embora o conhecimento dos mecanismos ativados por elementos da matriz extracelular em células de mamíferos esteja bastante avançado (revisado por Kim, et al, 2011), pouco é conhecido sobre as vias ativadas em T. cruzi durante sua adesão a ECM (Nde, et al, 2012 ou a seus elementos como laminina-1 (Giordano, et al, 1999), colágeno (Velge, et al, 1988) (Ouaissi, et al, 1984), heparan sulfato (Calvet, et al, 2003;Oliveira, et al, 2008;Bambino-Medeiros, et al, 2011), galectin-3 (Moody, et al, 2000 ou trombospondina .…”

“…A análise de redes de interações de proteínas relacionadas com a matriz extracelular, envolvendo ligantes de gp83 (membro das gp85/TS) indicaram que laminina e trombospondina são requeridas pelo parasita para sua internalização (Nde, et al, 2012). Nessa rede, Galectina-3 liga-se a mucinas de 45kDa e 30kDa presentes na superfície do parasita, (Moody, et al, 2000, Kleshchenko, et al,2004, sendo responsável pela interação entre a laminina da célula hospedeira e o parasita, facilitando a infecção.…”