《2014 T cell mediated suppression of neurotropic coronavirus replication in neural precursor cells》由会员分享，可在线阅读，更多相关《2014 T cell mediated suppression of neurotropic coronavirus replication in neural precursor cells（9页珍藏版）》请在金锄头文库上搜索。
1、T cell mediated suppression of neurotropic coronavirus replication in neural precursor cells Warren C. Plaisted a,b, Jason G. Weingera,b, Craig M. Walsha,b,c,d, Thomas E. Lanea,b,c,d,n aDepartment of Molecular Biology McBride et al., 2004; van Gorp et al., 2013; Yasuhara et al., 2006). Furthermore,
2、in murine and non-human primate models of the neuroinfl ammatory disease multiple sclerosis (MS) the ability of human NPCs to function as modulators of the immune system in addition to replacing lost or damaged neural cell populations has been suggested (Aharonowiz et al., 2008; Pluchino et al., 200
3、3, 2009). However, despite the clinical and histological benefi ts of NPC transplantation in pre-clinical animal models of neurologic disease, there is limited evidence addressing the capacity of neural grafts to act as reservoirs for viral replication. Studies using the non-polio enterovirus coxsac
4、kievirus B (CVB) demonstrate the ability of CVB to preferentially replicate in murine NPCs (Ruller et al., 2012). The ensuing carrier-state infection results in increased cell death and impaired differentiation potential in vitro, as well as infl ammation, microgliosis, and a variety of CNS developm
5、ental defects in vivo (Ruller et al., 2012; Tsueng et al., 2011). Intracerebral infection of neonates with murine cytomegalovirus (MCMV) results in the loss of neural stem cells and their neuronal progeny, as well as a decrease in the production of neurotrophins imperative to normal brain developmen
6、t (Mutnal et al., 2011). Borna disease virus (BDV) infection of human fetal human NPCs results in cell death upon differentiation and impaired neurogenesis (Brnic et al., 2012). Thus, the role of neural stem and progenitors as targets for a variety of neuroinvasive viruses is evident, while the cons
7、equences of infection within the context of cellular therapy remain to be elucidated. Complicating NPC-based therapies is the controversial issue of antigenicity of transplanted cells and immune-mediated recogni- tion. A growing body of evidence suggests NPCs are not immuno- privileged, as has previ
8、ously been reported (Hori et al., 2003). Indeed, we have shown that NPCs derived from post-natal C57BL/6 brains express the co-stimulatory molecules CD80 and CD86 and up-regulate major histocompatibility complex (MHC) molecules in response to the pro-infl ammatory cytokine interferon gamma (IFN-) (W
9、einger et al., 2012). Furthermore, allogeneic NPCs are rapidly rejected via a T cell mediated mechanism following intraspinaltransplantationintoMHC-mismatchedrecipients (Weinger et al., 2012). Similarly, human NPCs have the capacity to express MHCs I and II and induce Tcell proliferation (Goya et al
10、., 2011). The apparent antigenicity of NPCs suggests successful engraftment may require the use of immunomodulatory agents and lifelong suppression of the immune system, as with solid Contents lists available at ScienceDirect journal homepage: Virology 0042-6822/$-see front matter Jordan et al., 197
11、7; Wynn et al., 2010; Young et al., 2012). Therefore, it is imperative to understand the consequencesofneurotropicvirusinfectionofNPCsascell- replacement therapies continue to move into the clinic (Gupta et al., 2012; Riley et al., 2013). In this study, we demonstrate that cultured murine NPCs are i
12、nfected by the neurotropic JHM strain of mouse hepatitis virus (JHMV), which induces acute encephalomyelitis and chronic demyelination when injected intracranially into immunocompe- tent mice. JHMV-infected NPCs support replication that ultimately results in increased cell death over time. Important
13、ly, CD8 Tcells kill NPCs pulsed with viral-peptides, and JHMV replication in NPCs was suppressed, in part, by IFN-secreted from virus-spec- ifi c CD4 T cells. Results NPCs express the MHV receptor CEACAM1a and are infected by JHMV JHMV is a neurotropic coronavirus with relatively restricted tropism
14、for glial cells through recognition and binding to the receptor carcinoembryonic antigen-cell adhesion molecule 1a (CEACAM1a) (Hirai et al., 2010; Thorp and Gallagher, 2004). CEACAM1a expression in mouse tissues is widespread and can be detected on the surface of a variety of epithelial cells in the
15、 gastrointestinal, respiratory, and reproductive tracts, as well as on small vascular endothelia and hematopoietic cells (Hemmila et al., 2004). However, CEACAM1a expression is not ubiquitous, and although it is known to be located at the surface of resident cells of the CNS including glia, expressi
16、on by neural stem or progenitor cells has not been evaluated. To determine if NPCs derived from C57BL/6 transgenic mice engineered to express GFP (GFP-NPCs) express CEACAM1a, mRNA was isolated from cultured NPCs and receptor expression was evaluated by PCR. Using CEACAM1a-specifi c primers, PCR amplicons were detected in NPCs, as well as mixed splenocytes from C57BL/6 mice acting as controls (Fig. 1A), and nucleotide sequencing confi rmed homology with the specifi ed region of the gene (data no
