被惡性瘧原蟲感染的紅細胞（iRBC）在早期的免疫反應中，自然殺傷細胞（Natural killer cell，也譯作NK細胞）是被激活的，這表明NK細胞與先天性抗寄生蟲免疫反應有關。然而，NK細胞是否會直接識別iRBC，刺激iRBC是否需要輔助細胞呈遞信號或是溶解性因子，這些問題目前還不明確。

近日，德國蒂賓根大學熱帶醫(yī)學研究所 Meral Esen等人發(fā)現(xiàn)：被瘧原蟲感染的紅細胞會通過宿主表達Hsp70來引起NK細胞釋放顆粒酶B，結果被感染的紅細胞衰亡。相關論文發(fā)表在3月15日的美國《公共科學圖書館—綜合》（PLoS One）上。

在近期的研究中，研究人員開展了關于“宿主細胞膜偶聯(lián)的熱休克蛋白70（Hsp70）會引起NK細胞對iRBC的毒性”的研究，這些NK細胞來自與瘧疾病人捐贈的NK細胞以及培養(yǎng)的NK92細胞系。對于表達于iRBC細胞膜的Hsp70和HLA-E，以及可能性的活化的NK細胞受體（包括NKG2C和CD94），該研究運用了流式細胞術以及免疫印記對它們進行評估。

蛋白印跡、RT-PCR 以及elispot.html' target='_blank'>ELISPOT分析表明：顆粒酶B（GzmB）的產生及釋放都由沒有受過刺激的NK細胞，以及Hsp70肽（TKD）預先刺激的NK細胞所啟動。

研究結果表明，當iRBC細胞上沒有HLA-E卻有Hsp70時，會促進感染的宿主細胞成為了NK細胞調停的細胞毒性目標。iRBC與NK細胞的則引起了GzmB的釋放，當GzmB被攝取后，iRBC通過一個不依賴穿孔素而是由GzmB調節(jié)的機制導致衰亡。

結果表明，NK細胞對iRBC的活性可以被TKD肽特異性增強，也可以因為Hsp70被抑制而降低到基礎水平。因此，TKD可以作為一個革新性的免疫刺激物。

Plasmodium falciparum-Infected Erythrocytes Induce Granzyme B by NK Cells through Expression of Host-Hsp70

Evelyn Bttger, Gabriele Multhoff, Jürgen F. J. Kun, Meral Esen

In the early immune response to Plasmodium falciparum-infected erythrocytes （iRBC）, Natural Killer （NK） cells are activated, which suggests an important role in innate anti-parasitic immunity. However, it is not well understood whether NK cells directly recognize iRBC or whether stimulation of NK cells depends mainly on activating signals from accessory cells through cell-to-cell contact or soluble factors.In the present study, we investigated the influence of membrane-bound host Heat shock protein （Hsp） 70 in triggering cytotoxicity of NK cells from malaria-nave donors or the cell line NK92 against iRBC. Hsp70 and HLA-E membrane expression on iRBC and potential activatory NK cell receptors （NKG2C, CD94） were assessed by flow cytometry and immunoblot. Upon contact with iRBC, Granzyme B （GzmB） production and release was initiated by unstimulated and Hsp70-peptide （TKD） pre-stimulated NK cells, as determined by Western blot, RT-PCR and ELISPOT analysis. Eryptosis of iRBC was determined by Annexin V-staining.Our results suggest that presence of Hsp70 and absence of HLA-E on the membrane of iRBC prompt the infected host cells to become targets for NK cell-mediated cytotoxicity, as evidenced by impaired parasite development. Contact of iRBC with NK cells induced release of GzmB. We propose that following GzmB uptake, iRBC undergo eryptosis via a perforin-independent, GzmB-mediated mechanism.Since NK activity toward iRBC could be specifically enhanced by TKD peptide and abrogated to baseline levels by blocking Hsp70 exposure, we propose TKD as an innovative immunostimulatory agent to be tested as an adjunct to anti-parasitic treatments in vivo.