Signaling through Toll-Like Receptors Induces Murine Gammaherpesvirus 68 Reactivation In Vivo
Signaling through Toll-Like Receptors Induces Murine Gammaherpesvirus 68 Reactivation In Vivo
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DOI：
10.1128/jvi.01717-08
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发表时间：
2009-02-01
影响因子：
5.4
通讯作者：
Speck, Samuel H.
中科院分区：
文献类型：
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作者：
Gargano, Lisa M.;Forrest, J. Craig;Speck, Samuel H.
小鼠伽玛疱疹病毒68(MHV68)建立了小鼠的终生感染模型，并被用作模型病原体来研究病毒和宿主因素在慢性感染中的作用。慢性MHV68感染的维持，至少在一些潜伏期水库中，似乎取决于病毒从体内潜伏期重新激活的能力。然而，导致MHV68在体内重新激活的信号还没有得到很好的表征。Toll样受体(Toll-like Receptor，TLRs)通过识别微生物成分的特定模式，在天然免疫的激活过程中发挥重要作用。在本研究中，我们研究了TLR配体在体外和体内诱导MHV68重新激活的能力。用TLRs 3、4、5和9的配体刺激潜伏感染的B细胞株可增强MHV68的重新激活；用聚(I：C)、脂多糖、鞭毛蛋白或CpG DNA体外刺激潜伏感染的小鼠脾细胞，可使B细胞早期激活、B细胞增殖，并显著增加潜伏感染细胞重新激活病毒的频率。在体内，TLR刺激还诱导B细胞激活和MHV68重新激活，导致肺内病毒复制水平增加，这与MHV68特异性CD8(+)T细胞反应增加有关。重要的是，TLR刺激也导致了MHV68潜伏期的增加，这从体内特定TLR配体刺激2周后病毒基因组阳性细胞的增加可见一斑。因此，这些数据表明，TLR刺激可以推动MHV68从潜伏期重新激活，并表明周期性病原体暴露可能通过刺激病毒重新激活和重新播种潜伏库而有助于维持慢性伽马疱疹病毒感染的动态平衡。
Murine gammaherpesvirus 68 (MHV68) establishes a lifelong infection in mice and is used as a model pathogen to study the role of viral and host factors in chronic infection. The maintenance of chronic MHV68 infection, at least in some latency reservoirs, appears to be dependent on the capacity of the virus to reactivate from latency in vivo. However, the signals that lead to MHV68 reactivation in vivo are not well characterized. Toll-like receptors (TLRs), by recognizing the specific patterns of microbial components, play an essential role in the activation of innate immunity. In the present study, we investigated the capacity of TLR ligands to induce MHV68 reactivation, both in vitro and in vivo. The stimulation of latently infected B cell lines with ligands for TLRs 3, 4, 5, and 9 enhanced MHV68 reactivation; the ex vivo stimulation of latently infected primary splenocytes, recovered from infected mice, with poly(I:C), lipopolysaccharide, flagellin, or CpG DNA led to early B-cell activation, B-cell proliferation, and a significant increase in the frequency of latently infected cells reactivating the virus. In vivo TLR stimulation also induced B-cell activation and MHV68 reactivation, resulting in heightened levels of virus replication in the lungs which correlated with an increase in MHV68-specific CD8(+) T-cell responses. Importantly, TLR stimulation also led to an increase in MHV68 latency, as evidenced by an increase in viral genome-positive cells 2 weeks post-in vivo stimulation by specific TLR ligands. Thus, these data demonstrate that TLR stimulation can drive MHV68 reactivation from latency and suggests that periodic pathogen exposure may contribute to the homeostatic maintenance of chronic gammaherpesvirus infection through stimulating virus reactivation and reseeding latency reservoirs.