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.

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.

Macrophage-infectivity potentiator of Trypanosoma cruzi (TcMIP) is a new pro-type 1 immuno-stimulating protein for neonatal human cells and vaccines in mice.

This work identifies the protein "macrophage infectivity potentiator" of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth.