Ly6Chi inflammatory monocytes promote susceptibility to Leishmania donovani infection.
Ly6Chi inflammatory monocytes promote susceptibility to Leishmania donovani infection.
复制标题
Ly6Chi 炎症单核细胞促进杜氏利什曼原虫感染的易感性。
DOI：
10.1038/s41598-017-14935-3
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发表时间：
2017
影响因子：
4.6
通讯作者：
Satoskar,AbhayR
中科院分区：
文献类型：
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作者：
Terrazas,Cesar;Varikuti,Sanjay;Oghumu,Steve;Steinkamp,HeidiM;Ardic,Nurittin;Kimble,Jennifer;Nakhasi,Hira;Satoskar,AbhayR
淋巴齐炎性单核细胞（iMO）对宿主防御弓形虫病和疟疾至关重要，但它们在利什曼病中的作用尚不清楚。在这项研究中，我们报道了Ly6ChiiMOs在由多诺瓦利什曼原虫引起的内脏利什曼病（VL）中的有害作用。我们发现，在l期间，Ly6ChiiMOs持续被募集到脾脏和肝脏。多诺瓦尼感染，它们是寄生虫的优先目标。利用基于微阵列的基因表达谱，我们发现从感染的肝脏和脾脏分离的Ly6ChiiMOs具有不同的表型和激活谱。此外，我们还证明，在l - 1过程中，阻断Ly6ChiiMOs在肝脏和脾脏的募集。使用CCR2拮抗剂的donovani感染降低了脾脏中致病性IFN-γ/IL10双产生者CD4+ T细胞的频率，并导致肝脏和脾脏中寄生虫负荷的显著减少。使用STAT1−/−小鼠，我们发现STAT1在l期间介导Ly6ChiiMOs向器官募集中起关键作用。donovani感染和野生型Ly6ChiiMOs向STAT1 - / -受体的适应性转移使它们对疾病易感。我们的研究结果揭示了Ly6ChiiMOs在VL中促进寄生虫生存的意想不到的致病作用，并为VL期间针对该人群进行宿主定向治疗开辟了可能性。
Ly6Chiinflammatory monocytes (iMO) are critical for host defense against toxoplasmosis and malaria but their role in leishmaniasis is unclear. In this study, we report a detrimental role of Ly6ChiiMOs in visceral leishmaniasis (VL) caused byLeishmania donovani. We demonstrate that Ly6ChiiMOs are continuously recruited into the spleen and liver duringL. donovaniinfection and they are preferential targets for the parasite. Using microarray-based gene expression profiling, we show that Ly6ChiiMOs isolated from the infected liver and spleen have distinct phenotypic and activation profiles. Furthermore, we demonstrate that blocking the recruitment of Ly6ChiiMOs into the liver and spleen duringL. donovaniinfection using a CCR2 antagonist reduces the frequency of the pathogenic IFN-γ/IL10 dual producer CD4+ T cells in the spleen and leads to a significant reduction in parasite loads in the liver and spleen. Using STAT1−/− mice we show that STAT1 is critical for mediating the recruitment of Ly6ChiiMOs into organs duringL. donovaniinfection, and adaptive transfer of wild type Ly6ChiiMOs into STAT1−/− recipients renders them susceptible to disease. Our findings reveal an unexpected pathogenic role for Ly6ChiiMOs in promoting parasite survival in VL and open the possibility of targeting this population for host-directed therapy during VL.