Modulation of B cell responses by viruses

体液免疫(即产生特定抗体)可能是预防病毒感染的最重要的相关因素。为了完全有效，必须迅速产生抗体，并以足够的效价遏制感染。急性病毒通常会引发快速有效的抗体反应，从而清除感染。然而，为了逃避抗体的识别，许多持久性病毒已经发展出损害和延迟B细胞反应的机制。例如，人类的艾滋病毒或丙型肝炎病毒或小鼠的淋巴细胞性脉络膜脑膜炎病毒(LCMV)等病毒会产生微弱的晚期中和抗体反应。病毒用来调节B细胞反应的分子机制仍然不清楚。这项建议的具体目标是确定在这两种感染环境中驱动差异B细胞反应的持续和急性病毒诱导的介体和信号通路。我们有三个具体的目标：*目标1.识别差异激活的B细胞内在信号通路，以响应急性和持续的病毒感染。为了进一步了解B细胞在应对急性和慢性病毒感染时的差异激活途径，我们将对感染期间不同时间点分离的脾滤泡B细胞进行转录图谱分析。在培养的B细胞中，将通过药物抑制或基因敲除来针对差异激活的通路进行验证。*目标2.评估急性和持续病毒感染对B细胞代谢的影响。我们发现，在持续病毒感染期间，干扰素-I、IL-21和BAFF持续表达，导致脾B细胞的激活和存活增加，并产生非特异性多克隆抗体。然而，这些效应背后的确切细胞机制在很大程度上是未知的。为了解决这一点，我们将分析持续感染期间不同时间脾B细胞的代谢情况，并与急性感染进行比较。本研究还将探讨低氧诱导因子和mTOR的作用。目的3.探讨抑制性磷酸酶在病毒持续感染和急性感染过程中对B细胞生理的影响。在LCMV持续感染期间产生的细胞因子有助于激活非特异性B细胞，同时损害抗原特异性B细胞反应，提示B细胞受体(BCR)信号在这一表型中起作用。磷酸酶如PTEN和SHIP-1是BCR信号的重要调节者，因此我们将在急性和慢性病毒感染的背景下研究它们的调控。*本研究计划将增加我们对调节急性病毒抗体形成的分子途径以及持续病毒为延迟其产生和逃避其影响而采取的策略的理解。

Humoral immunity (i.e. the production of specific antibodies) is probably the most important correlate of protection against viral infections. To be fully effective, antibodies must be produced rapidly and in sufficient titers to curb the infection. Acute viruses usually trigger rapid and efficient antibody responses that clear the infection. However, to escape recognition by antibodies, many persistent viruses have developed mechanisms to impair and delay B cell responses. For example, viruses such as HIV or HCV in humans or the lymphocytic choriomeningitis virus (LCMV) in mice generate weak and late neutralizing antibody responses. The molecular mechanisms used by viruses to modulate B cell responses remain elusive. The specific goal of this proposal is to identify mediators and signaling pathways induced by persistent and acute viruses that drive differential B cell responses in these two infection contexts. We have three specific objectives:******Objective 1. Identify differentially activated B cell-intrinsic signaling pathways induced in response to acute and persistent virus infections. To gain further insight into the pathways that are differentially activated in B cells in response to acute and chronic viral infections, we will conduct transcriptomic profiling of splenic follicular B cells isolated at different time points during infection. Differentially activated pathways will be targeted using pharmacological inhibition or gene knockdown in cultured B cells for validation.******Objective 2. Assess the impact of acute versus persistent virus infection on B cell metabolism. We showed that IFN-I, IL-21 and BAFF expression is sustained during persistent virus infection leading to increased activation and survival of splenic B cells and production of non-specific polyclonal antibodies. However, the precise cellular mechanisms underlying these effects are largely unknown. To begin to address this point we will analyse the metabolism of splenic B cells at different times during persistent infection in comparison with acute infection. The contribution of hypoxia-inducible factors and mTOR will also be explored in this aim.******Objective 3. Investigate the involvement of inhibitory phosphatases in B cell physiology during persistent and acute virus infection. Cytokines produced during persistent LCMV infection contribute to the activation of non-specific B cells while impairing antigen-specific B cell responses suggesting a role for B cell receptor (BCR) signalling in this phenotype. Phosphatases such as PTEN and SHIP-1 are important regulators of BCR signaling, we will therefore investigate their regulation in the context of acute and chronic virus infection.******This research program will increase our understanding of the molecular pathways regulating antibody development against acute viruses and the strategies employed by persistent viruses to delay their production and escape their effects.**