Fontana Mary F, Baccarella Alyssa, Craft Joshua F, Boyle Michelle J, McIntyre Tara I, Wood Matthew D, Thorn Kurt S, Anidi Chioma, Bayat Aqieda, Chung Me Ree, Hamburger Rebecca, Kim Chris Y, Pearman Emily, Pham Jennifer, Tang Jia J, Boon Louis, Kamya Moses R, Dorsey Grant, Feeney Margaret E, Kim Charles C
Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, 94143, United States of America.
The Burnet Institute, Center for Biomedical Research, Melbourne, Australia.
PLoS One. 2016 Sep 1;11(9):e0162132. doi: 10.1371/journal.pone.0162132. eCollection 2016.
In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection.
在人类中，对疟原虫属的免疫通常表现为预防有症状疟疾（即“临床免疫”）而非预防感染（“无菌免疫”）。相比之下，感染疟原虫的小鼠会产生无菌免疫，这阻碍了对临床免疫机制基础的理解。在此，我们提出一种新模型，其中持续感染查巴迪疟原虫的小鼠尽管在数月内维持着明显的寄生虫负荷，但临床症状有限。对持续感染小鼠免疫反应的表征揭示了CD4 + T细胞耗竭的发展、白细胞介素-10产生的增加以及具有非典型表面表型的B细胞的扩增。此外，持续感染的小鼠循环中的非经典单核细胞显著增加，我们在长期接触疟原虫且无症状感染的人类中也观察到了这一现象。在药物清除感染后，先前持续感染的小鼠无法控制二次感染，这表明持续感染破坏了在急性感染小鼠模型中通常会产生的无菌免疫。本研究建立了一种无症状、持续性疟原虫感染的动物模型，该模型概括了长期接触疟原虫的人类免疫反应的几个核心方面。因此，它为剖析可能阻止无菌免疫发展并限制感染期间病理变化的免疫反应提供了一种新工具。
