Orchanian Stephanie B, Zolog Sebastian, Tomasello Julia, Malik Rijul, Shin Ji-Hun, Koshy Anita A, Lodoen Melissa B
Department of Molecular Biology and Biochemistry, University of California, Irvine, California, USA.
Institute for Immunology, University of California, Irvine, California, USA.
mBio. 2025 Jun 10:e0081025. doi: 10.1128/mbio.00810-25.
is a foodborne intracellular parasite that chronically infects the brain. Although infection elicits a protective immune response, the nature of the monocyte response in the immediate vicinity of parasites during initial brain infection is not well understood. By infecting mice with and comparing areas of the brain containing or not containing parasites, we found an increase in CCR2 monocytes, IBA1 myeloid cells, GFAP astrocytes, and CD68 signal near parasites in the brain, indicating immune cell infiltration and phagolysosomal activation in response to the infection. CCR2CD68 monocytes were specifically increased near tachyzoites with minimal localization of these cells near cysts in the brain. This monocyte response was also detected near parasite-interacted cells, identified using parasites that inject Cre recombinase into "interacted" cells of Ai6 CCR2 mice, enabling us to track these events . The chemokine CCL2 and its transcription factor NF-κB were also upregulated surrounding parasites in the brain; however, the effector protein GRA15, which sustains NF-κB activation in infected cells, was not required for CCL2 production, NF-κB activation, or myeloid cell recruitment to parasites in the brain. In contrast, active replication played a more significant role, as CCR2 monocytes were recruited to replication-competent but not replication-deficient delivered via intracranial injection into mice. These findings provide novel insights into the drivers of immune cell mobilization and activation in the brain during initial central nervous system infection and highlight the importance of parasite replication in this process.
is a brain-infecting parasite, and the mobilization of peripheral immune cells to the brain is critical for controlling infection. However, the initial events driving these cells to sites of infection in the brain are poorly understood. We show that peripheral myeloid immune cell recruitment and activation are specific to areas of the brain containing actively replicating parasites, which are capable of lysing host cells. This local immune response is characterized by focal chemokine production, myeloid cell recruitment, and the activation of phagolysosomal pathways. These highly localized host responses were independent of the parasite effector protein that induces NF-κB activation within infected cells, GRA15. However, the localized monocyte recruitment was dependent on live parasites and active parasite replication. This research highlights the importance of host cell sensing of parasite replication in the brain for immune control of infection.
是一种食源性细胞内寄生虫，可长期感染大脑。虽然感染会引发保护性免疫反应，但在初次脑部感染期间，寄生虫附近单核细胞反应的性质尚不清楚。通过用[寄生虫名称]感染小鼠，并比较大脑中含有或不含有寄生虫的区域，我们发现大脑中寄生虫附近的CCR2单核细胞、IBA1髓样细胞、GFAP星形胶质细胞和CD68信号增加，表明免疫细胞浸润和吞噬溶酶体激活以应对感染。CCR2 + CD68单核细胞在速殖子附近特异性增加，而这些细胞在大脑囊肿附近的定位最少。在寄生虫相互作用的细胞附近也检测到这种单核细胞反应，这些细胞是用将Cre重组酶注射到Ai6 CCR2小鼠的“相互作用”细胞中的[寄生虫名称]鉴定出来的，这使我们能够追踪这些事件。趋化因子CCL2及其转录因子NF-κB在大脑中寄生虫周围也上调；然而，在感染细胞中维持NF-κB激活的效应蛋白GRA15对于CCL2产生、NF-κB激活或髓样细胞向大脑中寄生虫的募集不是必需的。相比之下，活跃的[寄生虫名称]复制发挥了更重要的作用，因为CCR2单核细胞被募集到通过颅内注射递送至小鼠体内的具有复制能力但非复制缺陷的[寄生虫名称]。这些发现为初次[寄生虫名称]中枢神经系统感染期间大脑中免疫细胞动员和激活的驱动因素提供了新的见解，并强调了寄生虫复制在此过程中的重要性。
[寄生虫名称]是一种感染大脑的寄生虫，外周免疫细胞向大脑的动员对于控制[寄生虫名称]感染至关重要。然而，驱动这些细胞到达大脑中[寄生虫名称]感染部位的初始事件尚不清楚。我们表明，外周髓样免疫细胞的募集和激活特定于大脑中含有活跃复制寄生虫的区域，这些寄生虫能够裂解宿主细胞。这种局部免疫反应的特征是局部趋化因子产生、髓样细胞募集和吞噬溶酶体途径的激活。这些高度局部化的宿主反应独立于在感染细胞内诱导NF-κB激活的寄生虫效应蛋白GRA15。然而，局部单核细胞募集依赖于活寄生虫和活跃的寄生虫复制。这项研究强调了宿主细胞感知大脑中寄生虫复制对于[寄生虫名称]感染免疫控制的重要性。
