Trypanosoma cruzi, the etiological agent of Chagas disease, modulates induction of IL-17+CD4+ cells via inhibition of IL-6 signaling by gp-130 cleavage

PONCE, NE; SANMARCO, LM; AOKI MP

Simposio; Keystone symposia The Innate Immune Response in the Pathogenesis of Infectious Disease; 2013

Keystone Symposia board

During T. cruzi infection IL-6 mediates host defense and cell survival mainly through the activation of the transcription factor STAT3 via gp130, a shared signal-transducing receptor utilized by several IL-6 type cytokines. We have recently reported that cruzipain (Cz), the major secreted parasite cysteine protease, abolishes the IL-6 signaling in cardiomyocyte cultures resulting in an increased apoptotic rate. Here, we studied the impact on the inhibition of IL-6 signaling exerted by T. cruzi secreted proteases in different host cells. Considering that both, active and inactive Cz are released by the parasite during natural infection, murine spleen cells were pre-incubated with conditioned media (CM) obtained from trypomastigote supernatants treated with DTT (Cz activator) or without treatment, and then subjected to Th17 polarizing conditions (IL-6, TGF-â, anti-IFN-ã and anti-IL-4). We found that CM-DTT significantly reduced the percentage of CD4+IL-17+ cells, while non-treated CM increased the rate of this cell population. Moreover, CM-DTT treatment completely abolished the IL-6-induced p-STAT3 in splenocytes, whereas CM diminished but not completely abrogated the IL-6 signaling. The IL-6/gp130/STAT3 axis inhibition was also observed in spleen cells pre-incubated with native active Cz, but it was reverted when the enzyme was complexed with its parasite inhibitor, chagasin. To account for these observations, we found that Cz enzymatically cleaved recombinant human gp130 ectodomain, and induced the release of membrane-distal N-terminal domain of this receptor on human peripheral blood mononuclear cells. These results provide, for the first time, evidence that the parasite may modify the IL-6-induced immune response by means of gp130 cleavage in different host cells through the modulation of its cysteine protease activity.