DataSheet_6_Macrophage-infectivity potentiator of Trypanosoma cruzi (TcMIP) is a new pro-type 1 immuno-stimulating protein for neonatal human cells and vaccines in mice.pdf

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.

本研究揭示了三角锥虫 cruzi 的锥虫滋养体蛋白“巨噬细胞感染性增强剂”，该蛋白支持一种新型特性，即对新生儿细胞的促Ⅰ型免疫刺激活性。在其重组形式（rTcMIP）中，该蛋白可触发健康新生儿脐带血细胞在体外培养24小时后分泌趋化因子CCL2和CCL3。进一步刺激72小时，在添加IL-2和IL-18的培养液中，将导致干扰素γ的分泌。rTcMIP活性被蛋白酶处理完全消除，且与其肽基脯氨酰顺反异构酶酶活性无关。rTcMIP作为佐剂的作用在新生儿小鼠免疫接种模型中进行了体内研究，使用无细胞白喉-破伤风-百日咳疫苗（DTPa）或卵蛋白，并将其与经典铝佐剂进行比较。与后者相比，rTcMIP增加了针对多种抗原的IgG抗体反应，同时使抗体产生偏向Th-1依赖的IgG2a型。rTcMIP佐剂效应的幅度取决于抗原及铝的共存。然而，rTcMIP并未增加与铝结合的OVA的IgE反应。rTcMIP在新生儿细胞上的免疫刺激效应的发现，为作为新生儿疫苗的促Ⅰ型佐剂的潜在应用开辟了新的可能性。这进而可能促进更高效疫苗的开发，这些疫苗可以在出生时给予，以降低出生后几周内感染相关发病率和死亡率，而这一时期的发病率和死亡率最高。