Secretion by Trypanosoma cruzi of a peptidyl-prolyl cis-trans isomerase involved in cell infection.

Abstract

Macrophage infectivity potentiators are membrane proteins described as virulence factors in bacterial intracellular parasites, such as Legionella and Chlamydia. These factors share amino acid homology to eukaryotic peptidyl-prolyl cis-trans isomerases that are inhibited by FK506, an inhibitor of signal transduction in mammalian cells with potent immunosuppressor activity. We report here the characterization of a protein released into the culture medium by the infective stage of the protozoan intracellular parasite Trypanosoma cruzi. The protein possesses a peptidylprolyl cis-trans isomerase activity that is inhibited by FK506 and its non-immunosuppressing derivative L-685,818. The corresponding gene presents sequence homology with bacterial macrophage infectivity potentiators. The addition of the protein, produced heterologously in Escherichia coli, to cultures of trypomastigotes and simian epithelial or HeLa cells enhances invasion of the mammalian cells by the parasites. Antibodies raised in mice against the T.cruzi isomerase greatly reduce infectivity. A similar reduction of infectivity is obtained by addition to the cultures of FK506 and L-685,818. We concluded that the T.cruzi isomerase is involved in cell invasion.

Molecular basis of mammalian cell invasion by Trypanosoma cruzi

“…Surface antigens with metalloprotease activity, which are homologous to Leishmania gp63, were identified in MT and TCT and affinity-purified antibodies to these antigens inhibited host cell invasion by ∼50% (Cuevas et al 2003). Moro et al (1995) characterized a secreted T. cruzi protein with peptidyl-prolyl cis-trans isomerase activity, susceptible to inhibition by the immunosuppressant FK506 and related drugs, and showed that the addition of the recombinant protein to simian epithelial or HeLa cells enhances parasite invasion. The monomeric protein has a peptidyl-prolyl cis-trans isomerase core, encompassing the characteristic rotamase hydrophobic active site, and its mechanism of action may be the triggering of host cell signal, with or without the contribution of rotamase activity (Pereira et al 2002).…”

Knowledge to Predict Pathogens: Legionella pneumophila Lifecycle Critical Review Part I Uptake into Host Cells

“…The Mip sequence from 35 Legionella species was conserved at the amino acid level 82% to 99% [94]. Mip exhibits a peptidylprolyl cis/trans isomerase (PPIase) activity and belongs to the enzyme family of FK506-binding proteins (FKBP), also seen in Chlamydia trachomatis and Trypanosoma cruzi [95][96][97]. Amino acids involved in PPIase activity were found to be totally conserved [94].…”

FKBPs in bacterial infections

“…Also, protozoan parasites like T. cruzi and L. infantum were shown to possess Mip-like PPIases that are secreted into the culture supernatant (Debroy et al, 2006;Moro et al, 1995).…”

“…In T. cruzi, Mip-like protein facilitates invasion of mammalian epithelial cells (Moro et al, 1995). Interestingly, the degree of structural similarity between TcMip and Mip protein of L. pneumophila enables a partial compensation of the invasion deficiency of Mip-deficient T cruzi by recombinant Legionella-Mip protein (Pereira et al, 2002).…”

“…As chaperones and foldases PPIases are involved in diverse protein-protein interactions that are short lived, difficult to entangle, and pleiotropic in their biological impact on bacterial physiology. Hence, it is not surprising that PPIases also very often correlate with virulence in pathogenic bacteria (Alonzo et al, 2009;Behrens-Kneip, 2010;Moro et al, 1995;Obi et al, 2011). This has become even more evident since the identification of macrophage infectivity potentiator (Mip) of Legionella pneumophila, as the first virulence-associated PPIase, and has opened the way to the analysis of bacterial FKBPs under the aspect infections with implications in alternative drug design strategies Fischer et al, 1992Fischer et al, , Ünal et al, 2011Ünal and Steinert, 2014).…”