DataSheet_8_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.

本研究揭示了克氏锥虫前鞭毛体中的一种蛋白质“巨噬细胞感染性增强剂”，该蛋白质支持一种新的特性，即对新生儿细胞具有促进型1免疫刺激活性。在其重组形式（rTcMIP）中，该蛋白质通过在体外培养24小时后，触发健康新生儿脐带血细胞的趋化因子CCL2和CCL3的分泌。进一步的72小时刺激，在添加IL-2和IL-18的培养基中，导致干扰素-γ的分泌。rTcMIP的活性通过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作为佐剂的能力在新生儿小鼠免疫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，并与传统的铝佐剂进行了比较。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于Th-1依赖的IgG2a型别。rTcMIP佐剂效应的幅度取决于抗原和铝的共存。与此相反，rTcMIP并未增加与铝结合的卵蛋白引起的IgE反应。rTcMIP在新生儿细胞上的免疫刺激作用的发现为作为促进型1佐剂用于新生儿疫苗的潜在应用开辟了新的可能性。这反过来又可能促进开发更有效的疫苗，这些疫苗可以在出生时给予，以减少出生后第一周内感染相关的发病率和死亡率，而这一阶段的发病率和死亡率是最高的。