DataSheet_9_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.

本研究确定了美洲锥虫感染性滋养体中的蛋白质“巨噬细胞感染性增强剂”，该蛋白质支持一种新型属性，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，该蛋白质在体外培养24小时后可由健康新生儿脐带血细胞诱导CCL2和CCL3的分泌。进一步刺激72小时，在添加IL-2和IL-18的培养条件下，可诱导干扰素-γ的分泌。rTcMIP活性可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作为佐剂的作用在新生儿小鼠免疫模型中进行了体内研究，使用了无细胞白喉-破伤风-百日咳疫苗（DTPa）或卵蛋白，并将其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Th-1依赖的IgG2a型。rTcMIP佐剂效应的幅度因抗原和铝的共存而异。与添加铝的OVA结合相比，rTcMIP并未增加IgE反应。rTcMIP对新生儿细胞的免疫刺激作用的发现，为新生儿疫苗作为促进型1佐剂的潜在应用开辟了新的可能性。这进而可能促进开发出更有效的疫苗，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的发病率和死亡率，而在此期间，发病率和死亡率是最高的。