Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature.
Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature.
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DOI：
10.1371/journal.pntd.0009321
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发表时间：
2021-04
影响因子：
3.8
通讯作者：
Scott P
中科院分区：
文献类型：
--
作者：
Farias Amorim C;O Novais F;Nguyen BT;Nascimento MT;Lago J;Lago AS;Carvalho LP;Beiting DP;Scott P
皮肤利什曼病是一种由CD4+ T细胞控制的局部感染，该细胞在病变内产生IFN-γ。吸收到病变的吞噬细胞，如单核细胞，然后暴露于IFN-γ中，触发它们杀死细胞内寄生虫的能力。与此一致的是，患者病变的转录分析确定了干扰素刺激基因（ISG）特征。为了确定局部巴西乳杆菌感染是否会引发可能影响疾病的全身免疫反应，我们对巴西乳杆菌感染患者和健康对照者的血液进行了RNA测序（RNA-seq）。功能富集分析确定了ISG信号是患者血液中主要的转录反应。这种ISG特征与血液中单核细胞和巨噬细胞特异性标记基因的增加以及血清中IFN-γ水平的升高有关。在血液中也观察到细胞毒性特征，这是病变的主要特征，并与细胞溶解细胞丰度增加相关。因此，尽管差异表达基因（DEGs）的数量大幅减少，但系统地发现病变中存在两个转录特征。最后，我们发现利什曼病中deg和isg的数量与结核病（另一种局部感染）相似，但明显少于疟疾。相比之下，在结核或疟疾中没有发现细胞溶解特征和细胞溶解细胞丰度增加。我们的结果表明，系统特征可以反映什么是发生在利什曼病变。此外，血液单核细胞和巨噬细胞中ISG信号的存在提示了一种限制寄生虫全身传播的机制，并通过在病变进入之前预先激活细胞来加强寄生虫控制。由巴西利什曼原虫引起的皮肤利什曼病在皮肤病变中表现出两种主要的炎症反应：干扰素-γ (IFN-γ)介导的信号传导促进寄生虫控制，以及细胞毒性CD8+ T和NK细胞介导的细胞溶解，促进病理增加。为了确定这些反应是否仅限于皮肤病变，我们对皮肤利什曼病（CL）患者的血液进行了rna测序，并在外周血中检测了这两种转录特征。干扰素刺激基因的存在，以及循环的IFN-γ，表明保护性免疫反应并不局限于病变部位，而是发生在全身。这可能是一种确保寄生虫最佳控制的机制，既可以限制寄生虫的全身传播，又可以在寄生虫进入病变之前预先激活细胞杀死它们。与结核病（TB）或疟疾患者的血液相比，巴西疟原虫患者血液中的细胞溶解转录特征是唯一可检测到的，进一步强调了该途径在皮肤利什曼病中的重要性。综上所述，这些数据表明，这种局部感染具有可能影响疾病发展的全身性成分。
Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-γ within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-γ which triggers their ability to kill the intracellular parasites. Consistent with this, transcriptional analysis of patient lesions identified an interferon stimulated gene (ISG) signature. To determine whether localized L. braziliensis infection triggers a systemic immune response that may influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients and healthy controls. Functional enrichment analysis identified an ISG signature as the dominant transcriptional response in the blood of patients. This ISG signature was associated with an increase in monocyte- and macrophage-specific marker genes in the blood and elevated serum levels IFN-γ. A cytotoxicity signature, which is a dominant feature in the lesions, was also observed in the blood and correlated with an increased abundance of cytolytic cells. Thus, two transcriptional signatures present in lesions were found systemically, although with a substantially reduced number of differentially expressed genes (DEGs). Finally, we found that the number of DEGs and ISGs in leishmaniasis was similar to tuberculosis–another localized infection–but significantly less than observed in malaria. In contrast, the cytolytic signature and increased cytolytic cell abundance was not found in tuberculosis or malaria. Our results indicate that systemic signatures can reflect what is occurring in leishmanial lesions. Furthermore, the presence of an ISG signature in blood monocytes and macrophages suggests a mechanism to limit systemic spread of the parasite, as well as enhance parasite control by pre-activating cells prior to lesion entry. Cutaneous leishmaniasis caused by the protozoan Leishmania braziliensis exhibits two dominant inflammatory responses in cutaneous lesions: Interferon-γ (IFN-γ)-mediated signaling, which promotes parasite control, and cytolysis mediated by cytotoxic CD8+ T and NK cells, which promotes increased pathology. To determine if these responses were limited to cutaneous lesions, we performed RNA-seq on the blood of cutaneous leishmaniasis (CL) patients, and detected both transcriptional signatures in the peripheral blood. The presence of interferon stimulated genes, as well as circulating IFN-γ, suggests that protective immune responses are not limited to the lesion site, but are occurring systemically. This may be one mechanism to ensure optimal control of the parasites, both by limiting their systemic spread and by pre-activating cells to kill the parasites prior to entry into the lesions. The cytolytic transcriptional signature was uniquely detectable in the blood of L. braziliensis patients when compared to the blood of patients with tuberculosis (TB) or malaria, further emphasizing the importance of this pathway in cutaneous leishmaniasis. Taken together, these data suggest that this localized infection has a systemic component that may have an impact the development of the disease.
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通讯作者：
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