Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
J Virol. 2019 Apr 3;93(8). doi: 10.1128/JVI.01760-18. Print 2019 Apr 15.
Gammaherpesviruses are ubiquitous pathogens that are associated with B cell lymphomas. In the early stages of chronic infection, these viruses infect naive B cells and subsequently usurp the B cell differentiation process through the germinal center response to ensure latent infection of long-lived memory B cells. A unique feature of early gammaherpesvirus chronic infection is a robust differentiation of irrelevant, virus-nonspecific B cells with reactivities against self-antigens and antigens of other species. In contrast, protective, virus-specific humoral responses do not reach peak levels until a much later time. While several host factors are known to either promote or selectively restrict gammaherpesvirus-driven germinal center response, viral mechanisms that contribute to the irrelevant B cell response have not been defined. In this report we show that the expression and the enzymatic activity of the gammaherpesvirus-encoded conserved protein kinase selectively facilitates the irrelevant, but not virus-specific, B cell responses. Further, we show that lack of interleukin-1 (IL-1) receptor attenuates gammaherpesvirus-driven B cell differentiation and viral reactivation. Because germinal center B cells are thought to be the target of malignant transformation during gammaherpesvirus-driven lymphomagenesis, identification of host and viral factors that promote germinal center responses during gammaherpesvirus infection may offer an insight into the mechanism of gammaherpesvirus pathogenesis. Gammaherpesviruses are ubiquitous cancer-associated pathogens that usurp the B cell differentiation process to establish life-long latent infection in memory B cells. A unique feature of early gammaherpesvirus infection is the robust increase in differentiation of B cells that are not specific for viral antigens and instead encode antibodies that react with self-antigens and antigens of other species. Viral mechanisms that are involved in driving such irrelevant B cell differentiation are not known. Here, we show that gammaherpesvirus-encoded conserved protein kinase and host IL-1 signaling promote irrelevant B cell responses and gammaherpesvirus-driven germinal center responses, with the latter thought to be the target of viral transformation.
γ 疱疹病毒是普遍存在的病原体，与 B 细胞淋巴瘤有关。在慢性感染的早期阶段，这些病毒感染幼稚 B 细胞，随后通过生发中心反应篡夺 B 细胞分化过程，以确保潜伏感染长寿记忆 B 细胞。早期 γ 疱疹病毒慢性感染的一个独特特征是大量分化与病毒无关、针对自身抗原和其他物种抗原具有反应性的非特异性 B 细胞。相比之下，保护性、针对病毒的体液反应要到稍后时间才达到峰值水平。虽然已知有几个宿主因素可以促进或选择性限制 γ 疱疹病毒驱动的生发中心反应，但促进无关 B 细胞反应的病毒机制尚未确定。在本报告中，我们表明 γ 疱疹病毒编码的保守蛋白激酶的表达和酶活性选择性促进了无关但非特异性的 B 细胞反应。此外，我们表明缺乏白细胞介素 1（IL-1）受体可减弱 γ 疱疹病毒驱动的 B 细胞分化和病毒再激活。由于生发中心 B 细胞被认为是 γ 疱疹病毒驱动的淋巴瘤发生过程中恶性转化的靶标，因此确定宿主和病毒因素，这些因素可促进 γ 疱疹病毒感染期间生发中心反应，可能有助于了解 γ 疱疹病毒发病机制。γ 疱疹病毒是普遍存在的与癌症相关的病原体，它篡夺 B 细胞分化过程，在记忆 B 细胞中建立终身潜伏感染。早期 γ 疱疹病毒感染的一个独特特征是大量分化出针对病毒抗原不具有特异性的 B 细胞，而是编码与自身抗原和其他物种抗原反应的抗体。涉及驱动这种无关 B 细胞分化的病毒机制尚不清楚。在这里，我们表明 γ 疱疹病毒编码的保守蛋白激酶和宿主 IL-1 信号促进无关 B 细胞反应和 γ 疱疹病毒驱动的生发中心反应，后者被认为是病毒转化的靶标。
