Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Molecular Infection Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
PLoS Negl Trop Dis. 2024 Jul 22;18(7):e0012255. doi: 10.1371/journal.pntd.0012255. eCollection 2024 Jul.
Infection with the protozoan parasite Trypanosoma cruzi is causative for Chagas disease, which is a highly neglected tropical disease prevalent in Latin America. Humans are primary infected through vectorial transmission by blood-sucking triatomine bugs. The parasite enters the human host through mucous membranes or small skin lesions. Since keratinocytes are the predominant cell type in the epidermis, they play a critical role in detecting disruptions in homeostasis and aiding in pathogen elimination by the immune system in the human skin as alternative antigen-presenting cells. Interestingly, keratinocytes also act as a reservoir for T. cruzi, as the skin has been identified as a major site of persistent infection in mice with chronic Chagas disease. Moreover, there are reports of the emergence of T. cruzi amastigote nests in the skin of immunocompromised individuals who are experiencing reactivation of Chagas disease. This observation implies that the skin may serve as a site for persistent parasite presence during chronic human infection too and underscores the significance of investigating the interactions between T. cruzi and skin cells. Consequently, the primary objective of this study was to establish and characterize the infection kinetics in human primary epidermal keratinocytes (hPEK). Our investigation focused on surface molecules that either facilitated or hindered the activation of natural killer (NK) cells, which play a crucial role in controlling the infection. To simulate the in vivo situation in humans, an autologous co-culture model was developed to examine the interactions between T. cruzi infected keratinocytes and NK cells. We evaluated the degranulation, cytokine production, and cytotoxicity of NK cells in response to the infected keratinocytes. We observed a strong activation of NK cells by infected keratinocytes, despite minimal alterations in the expression of activating or inhibitory ligands on NK cell receptors. However, stimulation with recombinant interferon-gamma (IFN-γ), a cytokine known to be present in significant quantities during chronic T. cruzi infections in the host, resulted in a substantial upregulation of these ligands on primary keratinocytes. Overall, our findings suggest the crucial role of NK cells in controlling acute T. cruzi infection in the upper layer of the skin and shed light on keratinocytes as potential initial targets of infection.
感染原生动物寄生虫克氏锥虫可导致恰加斯病，这是一种在拉丁美洲流行的高度被忽视的热带病。人类主要通过吸血的三锥虫通过媒介传播感染。寄生虫通过粘膜或小的皮肤损伤进入人体宿主。由于角蛋白细胞是表皮中的主要细胞类型，它们在检测内稳态的破坏和帮助免疫系统消除人类皮肤中的病原体方面发挥着关键作用，作为替代的抗原呈递细胞。有趣的是，角蛋白细胞也作为克氏锥虫的储库，因为皮肤已被确定为慢性恰加斯病小鼠中持续感染的主要部位。此外，有报道称在免疫功能低下的个体中，出现了克氏锥虫无鞭毛体巢，这些个体正在经历恰加斯病的再激活。这一观察结果表明，在慢性人类感染期间，皮肤也可能是寄生虫持续存在的部位，并强调了研究克氏锥虫与皮肤细胞相互作用的重要性。因此，本研究的主要目标是建立和表征人原代表皮角质形成细胞（hPEK）中的感染动力学。我们的研究重点是促进或阻碍自然杀伤（NK）细胞激活的表面分子，NK 细胞在控制感染中起着至关重要的作用。为了模拟人类体内的情况，开发了一种自体共培养模型来研究感染的角质形成细胞与 NK 细胞之间的相互作用。我们评估了 NK 细胞对感染的角质形成细胞的脱颗粒、细胞因子产生和细胞毒性。我们观察到感染的角质形成细胞强烈激活 NK 细胞，尽管 NK 细胞受体上的激活或抑制配体的表达变化很小。然而，用重组干扰素-γ（IFN-γ）刺激，一种已知在宿主中慢性克氏锥虫感染期间大量存在的细胞因子，导致主要角质形成细胞上这些配体的大量上调。总的来说，我们的发现表明 NK 细胞在控制皮肤上层的急性克氏锥虫感染中起着至关重要的作用，并揭示了角蛋白细胞作为潜在的初始感染靶点。
