Mena I, Perry C M, Harkins S, Rodriguez F, Gebhard J, Whitton J L
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California, USA.
Am J Pathol. 1999 Oct;155(4):1205-15. doi: 10.1016/S0002-9440(10)65223-6.
Coxsackieviruses are important human pathogens, frequently causing myocarditis, pancreatitis, and a variety of less severe diseases. B lymphocytes appear central to the interaction between these viruses and their mammalian hosts, because agammaglobulinemic humans, genetically incapable of antibody production, are susceptible to chronic infections by coxsackieviruses and related enteroviruses, such as poliovirus and echovirus. However, recent studies show that Type B coxsackievirus (CVB) infects B lymphocytes soon after infection, suggesting the possibility that these cells may play some role in virus dissemination and/or that the virus may be able to modulate the host immune response. We analyzed the role of B lymphocytes in CVB infection and confirmed that CVB infects B lymphocytes, and extended these findings to show that this is a productive infection involving approximately 1 to 10% of the cells; however, infectious center assays show that other splenocytes are infected at approximately the same frequency. Virus is readily detectable by in situ hybridization in the spleen of immunocompetent mice but is difficult to detect in mice deficient in B cells (BcKO mice), consistent with much of the splenic signal being the result of B cell infection. Surprisingly, given the extent of their infection, B cells express barely detectable levels of the murine coxsackievirus-adenovirus receptor (mCAR), suggesting that another means of cell entry may be used. We found no evidence of B cell depletion following CVB infection, indicating that this is not the explanation for the transient immunosuppression previously reported. Virus replication and dissemination are slightly delayed in BcKO mice, consistent with B cells' playing a role as an important early target of infection and/or a means to distribute the virus to many tissues. In addition, we show that BcKO mice recapitulate a central feature of human agammaglobulinemia: CVB establishes chronic infection in a variety of organs (heart, liver, brain, kidney, lung, pancreas, spleen). In most of these tissues the viral titers remain high (10(5)-10(8) plaque forming units (pfu) per gram of tissue) for the life of the mouse, and in several there is severe pathology, particularly severe myocardial fibrosis with ventricular dilation, reminiscent of the dilated cardiomyopathy seen in humans with chronic enteroviral myocarditis. Transfer of B and/or T cells from non-immune mice had no discernible effect, whereas equivalent transfers from immune mice often resulted in transient or permanent disappearance of detectable CVB.
柯萨奇病毒是重要的人类病原体，常引发心肌炎、胰腺炎以及多种不太严重的疾病。B淋巴细胞似乎在这些病毒与其哺乳动物宿主之间的相互作用中起核心作用，因为遗传性无法产生抗体的无丙种球蛋白血症人类易受柯萨奇病毒及相关肠道病毒（如脊髓灰质炎病毒和埃可病毒）的慢性感染。然而，最近的研究表明，B型柯萨奇病毒（CVB）在感染后不久就会感染B淋巴细胞，这表明这些细胞可能在病毒传播中发挥某种作用，和/或病毒可能能够调节宿主免疫反应。我们分析了B淋巴细胞在CVB感染中的作用，证实CVB感染B淋巴细胞，并进一步发现这是一种增殖性感染，约1%至10%的细胞会被感染；然而，感染中心分析表明其他脾细胞被感染的频率大致相同。在免疫活性小鼠的脾脏中，通过原位杂交很容易检测到病毒，但在B细胞缺陷小鼠（BcKO小鼠）中很难检测到，这与大部分脾脏信号是B细胞感染的结果一致。令人惊讶的是，尽管B细胞被感染的程度很高，但它们表达的小鼠柯萨奇病毒 - 腺病毒受体（mCAR）水平几乎检测不到，这表明可能使用了另一种细胞进入方式。我们没有发现CVB感染后B细胞耗竭的证据，这表明这不是先前报道的短暂免疫抑制的原因。BcKO小鼠中的病毒复制和传播略有延迟，这与B细胞作为重要的早期感染靶点和/或将病毒传播到许多组织的一种方式的作用一致。此外，我们表明BcKO小鼠重现了人类无丙种球蛋白血症的一个核心特征：CVB在多种器官（心脏、肝脏、大脑、肾脏、肺、胰腺、脾脏）中建立慢性感染。在大多数这些组织中，病毒滴度在小鼠的整个生命周期内都保持很高（每克组织10^5 - 10^8 噬斑形成单位（pfu）），并且在几个组织中有严重的病理变化，特别是伴有心室扩张的严重心肌纤维化，让人联想到患有慢性肠道病毒性心肌炎的人类中出现的扩张型心肌病。从非免疫小鼠转移B细胞和/或T细胞没有明显效果，而从免疫小鼠进行同等转移通常会导致可检测到的CVB短暂或永久消失。
