Ioannidis Lisa J, Nie Catherine Q, Ly Ann, Ryg-Cornejo Victoria, Chiu Chris Y, Hansen Diana S
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia; and.
Office for Research Ethics and Integrity, The University of Melbourne, Parkville, Victoria 3010, Australia.
J Immunol. 2016 Feb 1;196(3):1227-38. doi: 10.4049/jimmunol.1501562. Epub 2015 Dec 30.
CXCL10, or IFN-γ-inducible protein 10, is a biomarker associated with increased risk for Plasmodium falciparum-mediated cerebral malaria (CM). Consistent with this, we have previously shown that CXCL10 neutralization or genetic deletion alleviates brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM. In addition to organ-specific effects, the absence of CXCL10 during infection was also found to reduce parasite biomass. To identify the cellular sources of CXCL10 responsible for these processes, we irradiated and reconstituted wild-type (WT) and CXCL10(-/-) mice with bone marrow from either WT or CXCL10(-/-) mice. Similar to CXCL10(-/-) mice, chimeras unable to express CXCL10 in hematopoietic-derived cells controlled infection more efficiently than WT controls. In contrast, expression of CXCL10 in knockout mice reconstituted with WT bone marrow resulted in high parasite biomass levels, higher brain parasite and leukocyte sequestration rates, and increased susceptibility to CM. Neutrophils and inflammatory monocytes were identified as the main cellular sources of CXCL10 responsible for the induction of these processes. The improved control of parasitemia observed in the absence of CXCL10-mediated trafficking was associated with a preferential accumulation of CXCR3(+)CD4(+) T follicular helper cells in the spleen and enhanced Ab responses to infection. These results are consistent with the notion that some inflammatory responses elicited in response to malaria infection contribute to the development of high parasite densities involved in the induction of severe disease in target organs.
CXCL10，即干扰素γ诱导蛋白10，是一种与恶性疟原虫介导的脑型疟疾（CM）风险增加相关的生物标志物。与此一致的是，我们之前已经表明，CXCL10的中和或基因缺失可减轻脑内血管炎症，并保护感染伯氏疟原虫ANKA的小鼠免受CM侵害。除了器官特异性作用外，还发现感染期间缺乏CXCL10会减少寄生虫数量。为了确定负责这些过程的CXCL10的细胞来源，我们用来自野生型（WT）或CXCL10（-/-）小鼠的骨髓对WT和CXCL10（-/-）小鼠进行照射和重建。与CXCL10（-/-）小鼠相似，造血来源细胞中无法表达CXCL10的嵌合体比WT对照更有效地控制感染。相反，用WT骨髓重建的基因敲除小鼠中CXCL10的表达导致寄生虫数量水平升高、脑内寄生虫和白细胞滞留率更高以及对CM的易感性增加。中性粒细胞和炎性单核细胞被确定为负责诱导这些过程的CXCL10的主要细胞来源。在没有CXCL10介导的运输的情况下观察到的对寄生虫血症的更好控制与脾脏中CXCR3（+）CD4（+）T滤泡辅助细胞的优先积累以及对感染的抗体反应增强有关。这些结果与以下观点一致，即对疟疾感染引发的一些炎症反应有助于在靶器官中诱导严重疾病的高寄生虫密度的发展。
