Role of HSP65 in host protection against intracellular protozoan infection.

我们曾报道过宿主65 kDa热休克蛋白（heat shock protein，HSP 65）的诱导与弓形虫（Toxoplasma gondii，T）感染的保护作用密切相关，T细胞尤其是γ δ T细胞在保护作用和HSP 65表达中起重要作用，弓形虫感染可诱导腹腔巨噬细胞表达HSP 65，γ δ T细胞耗竭可导致HSP 65表达明显减弱。该T细胞亚群分泌IFN-γ和TNF-α，如通过使用RT-PCR方法测定的。已知这些细胞因子激活巨噬细胞。在感染前用相应抗体中和这些细胞因子抑制HSP 65表达，表明γ δ T细胞引起的HSP 65表达依赖于这些细胞因子。我们推测，HSP 65参与保护巨噬细胞的手段，在符合其天然的作用，作为“分子伴侣”。腹腔巨噬细胞和巨噬细胞系J774细胞在体外感染弓形虫后发生凋亡。这些细胞在上述细胞因子的诱导下表达HSP 65，从而防止细胞凋亡。然而，这种作用通过添加该蛋白的反义寡核苷酸而逆转。以上结果表明，HSP 65抑制巨噬细胞凋亡，从而起到保护作用;在感染硕大利什曼原虫和克氏锥虫的小鼠中，HSP 65的表达与保护性免疫也存在类似的关系。

We previously reported that induction of host 65 kDa heat shock protein (HSP65) closely correlates with protection against Toxoplasma gondii (T.gondii) infection, and T cells, especially gammadelta T cells, play an important role in protection and HSP65 expression.T.gondii infection induces HSP65 expression in peritoneal macrophages and depletion of gammadelta T cells resulted in marked attenuation of its espression. This T cell subset secretes IFN-gamma and TNF-alpha as determined by using RT-PCR method. These cytokines are known to activate macrophages. Neutralization of these cytokines with corresponding antibodies prior to infection suppresses HSP65 expression, indicating that HSP65 expression attributed by gammadelta T cells is dependent on these cytokines. We speculate that HSP65 participates in protection by means of preservation of macrophages, in coincident with its native role as "molecular chaperon". Peritoneal macrophages and macrophage cell line, J774 cells infected in vitro with T.gondii undergo apoptosis. Expression of HSP65 on these cells, being induced with above cytokines, prevents them from apoptosis. However, this effect is reversed by the addition of antisense oligonucleotide for this protein. These results indicate that HSP65 prevent apoptosis of macrophages, which contributes to protection.A similar relationship between protective immunity and HSP65 expression was also seen in mice infected with Leishmania major and Trypanosoma cruzi.