Manickam Cordelia, Rajakumar Premeela, Wachtman Lynn, Kramer Joshua A, Martinot Amanda J, Varner Valerie, Giavedoni Luis D, Reeves R Keith
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
J Virol. 2016 Sep 29;90(20):9153-62. doi: 10.1128/JVI.01051-16. Print 2016 Oct 15.
Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R = 0.698; P = 0.015) and liver (R = 0.567; P = 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-γ) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection.
Hepatitis C virus (HCV) infection has created a global health crisis, and despite new effective antivirals, it is still a leading cause of liver disease and death worldwide. Recent evidence suggests that innate immunity may be a potential therapeutic target for HCV, but it may also be a correlate of increased disease. Due to a lack of access to human tissues with acute HCV infection, in this study we evaluated the role of innate immunity in resolving infection with a hepacivirus, GBV-B, in common marmosets. Collectively, our data suggest that NK cell and DC mobilization in acute hepacivirus infection can dampen virus replication but also regulate acute and chronic liver damage. How these two opposing effects on the host may be modulated in future therapeutic and vaccine approaches warrants further study.
尽管组织特异性固有免疫在塑造适应性免疫反应、病毒清除和基于免疫的炎症中具有重要作用，但由于无法获取急性感染组织，丙型肝炎病毒（HCV）感染的组织特异性固有免疫仍未得到充分表征。在本研究中，我们评估了自然杀伤（NK）细胞、髓样（mDCs）和浆细胞样（pDCs）树突状细胞对普通狨猴感染另一种更快清除的肝炎病毒GB病毒B（GBV - B）后病毒复制控制和病毒诱导病理的影响。高血浆和肝脏病毒载量以及严重肝炎是急性GBV - B感染的特征，虽然病毒血症通常在感染后2至3个月清除，但肝炎和肝纤维化在清除后仍持续存在。与病毒载量峰值和肝脏病理相一致，肝脏中NK细胞、mDCs和pDCs的水平增加了多达3倍。尽管外周固有细胞没有明显的数量变化，但循环NK细胞表现出穿孔素和Ki67表达水平增加以及CXCR3表面表达增加。这些数据表明，NK细胞的武装和增殖增加以及组织迁移可能与急性感染期间流入肝脏有关。事实上，肝脏中的NK细胞频率与血浆（R = 0.698；P = 0.015）和肝脏（R = 0.567；P = 0.057）病毒载量呈正相关。最后，与NK细胞和DCs相关的可溶性因子，包括γ干扰素（IFN -γ）和RANTES，在急性感染中增加，并且也与病毒载量和肝炎有关。总体而言，这些发现表明局部和循环固有免疫反应的动员与急性病毒诱导的肝炎有关，并且可能与GBV - B感染的清除有关，我们的结果可能为HCV感染中的类似机制提供见解。
丙型肝炎病毒（HCV）感染已造成全球健康危机，尽管有新的有效抗病毒药物，但它仍是全球肝病和死亡的主要原因。最近的证据表明，固有免疫可能是HCV的潜在治疗靶点，但它也可能与疾病增加相关。由于无法获取急性HCV感染的人体组织，在本研究中我们评估了固有免疫在普通狨猴中解决肝炎病毒GBV - B感染中的作用。总体而言，我们的数据表明急性肝炎病毒感染中NK细胞和DC的动员可以抑制病毒复制，但也调节急性和慢性肝损伤。在未来的治疗和疫苗方法中如何调节对宿主的这两种相反作用值得进一步研究。
