The macrophage infectivity potentiator of Trypanosoma cruzi induces innate IFN-γ and TNF-α production by human neonatal and adult blood cells through TLR2/1 and TLR4

Abstract

We previously identified the recombinant (r) macrophage (M) infectivity (I) potentiator (P) of the protozoan parasite Trypanosoma cruzi (Tc) (rTcMIP) as an immuno-stimulatory protein that induces the release of IFN-γ, CCL2 and CCL3 by human cord blood cells. These cytokines and chemokines are important to direct a type 1 adaptive immune response. rTcMIP also increased the Ab response and favored the production of the Th1-related isotype IgG2a in mouse models of neonatal vaccination, indicating that rTcMIP could be used as a vaccine adjuvant to enhance T and B cell responses. In the present study, we used cord and adult blood cells, and isolated NK cells and human monocytes to investigate the pathways and to decipher the mechanism of action of the recombinant rTcMIP. We found that rTcMIP engaged TLR1/2 and TLR4 independently of CD14 and activated the MyD88, but not the TRIF, pathway to induce IFN-γ production by IL-15-primed NK cells, and TNF-α secretion by monocytes and myeloid dendritic cells. Our results also indicated that TNF-α boosted IFN-γ expression. Though cord blood cells displayed lower responses than adult cells, our results allow to consider rTcMIP as a potential pro-type 1 adjuvant that might be associated to vaccines administered in early life or later.

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low Trypanosoma cruzi parasite exposure

“…Blockade of TLR2 resulted in more T. cruzi replication ( Figure 5A ) likely due to a reduction in TLR2-mediated signaling and cytokines production ( Figure 6 ). Interestingly, we have not detected significant overexpression of TLR4, reported to induce IFN-γ and TNF-α production in human cord blood cells after stimulation a recombinant T. cruzi macrophage infectivity potentiator (TcMIP) ( Ait Djebbara et al, 2023 ). Likewise, we have not observed an increase in the level of nuclear factor kappa B (NF-κB) RNA transcripts, a molecule shown to be activated in placental explants via TLRs signaling pathways ( Liempi et al, 2019 ).…”

“…T. cruzi molecules such as surface glycoinositolphospholipids (GPIs) and parasite DNA/RNA sequences can be sensed by TLRs ( Macaluso et al, 2023 ). In fact, several investigators have shown the significance and involvement of TLRs in the control of T. cruzi infection ( Caetano et al, 2011 ; Castillo et al, 2017b ; Queiroga et al, 2021 ; Ait Djebbara et al, 2023 ).…”

“…Several animal and ex vivo models have been used to study CD congenital transmission ( Avalos-Borges et al, 2022 ). For instance, modulation of the NF-κB and Toll-like receptors (TLRs) pathways, as well as the role of the placental barrier integrity in parasite infection have been evaluated in chorionic villi explants ( Diaz-Lujan et al, 2016 ; Liempi et al, 2016 ; Castillo et al, 2017a , b ) and cord blood cells ( Ait Djebbara et al, 2023 ). Yet, the ability to reproduce parasite infection in an environment that resembles the complex architecture of the human placenta continues to be a challenge for the field ( Barrila et al, 2018 ; Torres-Vargas et al, 2018 ; Ander et al, 2019 ).…”

Dynamic m6A profiles reveal the role of YTHDC2‐TLR2 signaling axis in Talaromyces marneffei infection

“…Even Katalin et al reported that m 6 A modifications suppress the ability of RNA to stimulate TLR3, TLR7, and TLR8, 38 they did not uncover the m 6 A-regulated expression level of TLR2, and our findings fill this knowledge gap. In fact, TLR2 is regulated by various mechanisms like infection and gut microbes, [39][40][41] and we have just discovered that m 6 A might be a regulatory mechanism during the TM infection process. Previous studies have shown that YTHDC2 primarily regulates RNA degradation through m 6 A modification.…”

Monocytes from Uninfected Neonates Born to Trypanosoma cruzi-Infected Mothers Display Upregulated Capacity to Produce TNF-α and to Control Infection in Association with Maternally Transferred Antibodies

“…Transplacental transfer of sensitizing T. cruzi components from the infected mother to her fetus is another possibility [ 26 ], although molecules implicated have not yet been identified. As TNF-a expression is critically induced by histone methylation triggered by the TLR4 ligand LPS [ 31 ] and as T. cruzi expresses TLR4 ligands [ 32 , 33 ], we may wonder if such molecules might be transferred from the infected mother to prime fetal monocytes. We cannot discard the potential effect of IgG and/or T. cruzi -specific Abs transferred from the mother.…”