This finding is in agreement with PI-103 others, which showed that human TSP-1 interacts with HuCRT and a co-receptor. NHS-biotin pre-labeling, which does not penetrate the parasite membrane, showed that T. cruzi has a 48 kDa TcCRT protein on its surface that interacts with TSP-1 and NTSP. Our observation that TSP-1 interacts with TcCRT located on the membrane of the parasite is also in agreement with the contemporary knowledge that CRT, which was previously thought to be exclusively intracellular, is also expressed on the surface of the parasite. Its role in the process of infection of those parasites remains unknown. Here we show that surface TcCRT is a virulent factor that interacts with host TSP-1 to enhance cellular infection by T. cruzi. TSP-1 and NTSP interacted with a 48 kDa protein on the surface of T. cruzi trypomastigotes that was identified as TcCRT. This protein is of parasite origin because we showed in pulse chase experiments that a radiolabeled nascent parasite surface protein of 48 kDa interacted with both full length TSP-1 and NTSP. The interaction of the TcCRT with NTSP is supported by previous findings which showed that HuCRT interacts with the N-terminal domain of TSP-1. The molecular interaction between TcCRT and TSP-1 remains unknown. The elucidation of the molecular interaction between the two molecules will enhance our understanding of the molecular pathogenesis of T. cruzi and also lead to the development of molecular strategies to reduce T. cruzi infection. Anti-TcCRT monospecific polyclonal IgG antibodies interact strongly with TcCRT in total parasite lysate, solubilized parasite membrane proteins, TcCRT pulled down by TSP-1 or NTSP and with the surface of invasive T. cruzi trypomastigotes. This further confirms the presence of TcCRT on the surface of the parasite that interacts with TSP-1. Anti-TcCRT also shows a weak interaction with a protein of about 85 kDa which might be complexed TcCRT or a protein that shares a common epitope with TcCRT. In order to explore the significance of host TSP-1 and TcCRT in cellular infection by T. cruzi, we used TSP-1 KO MEF and WT MEF in our infection assays. We showed that the presence of host TSP-1 and parasite surface TcCRT are important for MEF cellular infection by T. cruzi. The significance of surface TcCRT in enhancing cellular infection by T. cruzi was supported by the fact that specific antibodies to TcCRT significantly reduced cellular infection. The observation of T. cruzi infection in the absence of TSP-1 indicates that there are other mechanisms independent of TcCRT-TSP-1 that are involved in the process of T. cruzi infection; but this does not negate the importance of this interaction during T. cruzi infection. The identification of TcCRT as a virulent factor expressed on the surface of the parasite can be exploited to provide new insights into the molecular mechanisms of cellular infection by T. cruzi. TcCRT expression on the parasite surface may modulate the vertebrate complement system as an immune escape mechanism.