Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
Front Cell Infect Microbiol. 2022 Mar 24;12:800395. doi: 10.3389/fcimb.2022.800395. eCollection 2022.
During the acute phase of Chagas disease, circulation through the bloodstream leads to high tissue parasitism in the host. In primary lymphoid organs, progenitor cell reduction paralleled transient immunosuppression. Herein we showed that acute oral infection in mice promotes diffuse parasitism in bone marrow cells at 14 and 21 days post-infection (dpi), with perivascular regions, intravascular regions, and regions near the bone being target sites of parasite replication. Phenotypic analysis of hematopoietic differentiation in the bone marrow of infected mice showed that the cell number in the tissue is decreased (lineage-negative and lineage-positive cells). Interestingly, analysis of hematopoietic branching points showed that hematopoietic stem and progenitor cells (HSPCs) were significantly increased at 14 dpi. In addition, the pool of progenitors with stem plasticity (HSC-MPP3), as well as multipotent progenitors (MPPs) such as MPP4, also showed this pattern of increase. In contrast, subsequent progenitors that arise from MPPs, such as common lymphoid progenitors (CLPs), lymphoid-primed MPPs (LMPPs), and myeloid progenitors, were not enhanced; conversely, all presented numeric decline. Annexin V staining revealed that cell death increase in the initial hematopoietic branching point probably is not linked to CLPs and that myeloid progenitors decreased at 14 and 21 dpi. In parallel, our investigation provided clues that myeloid progenitor decrease could be associated with an atypical expression of Sca-1 in this population leading to a remarkable increase on LSK-like cells at 14 dpi within the HSPC compartment. Finally, these results led us to investigate HSPC presence in the spleen as a phenomenon triggered during emergency hematopoiesis due to mobilization or expansion of these cells in extramedullary sites. Splenocyte analysis showed a progressive increase in HSPCs between 14 and 21 dpi. Altogether, our study shows that the bone marrow is a target tissue in orally infected mice, leading to a hematopoietic disturbance with LSK-like cell bias accounting on HSPCs possibly affecting myeloid progenitor numbers. The LMPP and CLP reduction converges with defective thymocyte development. Lastly, it is tempting to speculate that the extramedullary hematopoiesis seen in the spleen is a mechanism involved in the hematological maintenance reported during the acute phase of oral infection.
在恰加斯病的急性期，循环血流导致宿主组织中的寄生虫大量繁殖。在初级淋巴器官中，祖细胞减少与短暂的免疫抑制平行。在此，我们表明，在感染后的第 14 和 21 天，急性口服感染会促进骨髓细胞中的弥散性寄生虫感染，血管周围区域、血管内区域和靠近骨骼的区域是寄生虫复制的靶位。对感染小鼠骨髓中造血分化的表型分析表明，组织中的细胞数量减少（谱系阴性和谱系阳性细胞）。有趣的是，造血分支点分析表明，在 14 dpi 时，造血干细胞和祖细胞（HSPCs）显著增加。此外，具有干细胞可塑性的祖细胞（HSC-MPP3）以及多能祖细胞（如 MPP4）也表现出这种增加模式。相反，来自 MPPs 的后续祖细胞，如共同淋巴祖细胞（CLPs）、淋巴样前体 MPPs（LMPPs）和髓系祖细胞，则没有增强；相反，它们的数量都有所下降。 Annexin V 染色显示，初始造血分支点的细胞死亡增加可能与 CLPs 无关，14 和 21 dpi 时髓系祖细胞减少。同时，我们的研究提供了线索，表明髓系祖细胞的减少可能与该群体中 Sca-1 的异常表达有关，这导致在 14 dpi 时 HSPC 区室中 LSK 样细胞显著增加。最后，这些结果促使我们研究脾脏中 HSPC 的存在，这是由于骨髓外部位这些细胞的动员或扩增而引发的应急造血现象。脾细胞分析显示，在 14 至 21 dpi 期间，HSPC 逐渐增加。总之，我们的研究表明，骨髓是感染小鼠的靶组织，导致造血紊乱，LSK 样细胞偏向于 HSPC，可能影响髓系祖细胞数量。LMPP 和 CLP 的减少与胸腺细胞发育缺陷相吻合。最后，人们不禁推测，脾脏中观察到的骨髓外造血是参与口服感染急性期报道的血液维持的一种机制。
