TH1 and TH2 Responses in Viral Immunity

流感病毒引起呼吸道感染，导致世界各地的发病率和死亡率。病毒感染呼吸道上皮，并在两天内迅速复制至峰值水平。它最终通过强烈的细胞免疫反应从肺部清除。在人类和小鼠中，流感病毒引发强烈的细胞反应。令人惊讶的是，流感病毒是一个非常差的体外DC成熟刺激物，因为病毒NS1蛋白抑制成熟过程。然而，如果DCs预先暴露于干扰素，细胞可以克服病毒拮抗作用并产生强烈反应。为了更好地了解体内产生免疫的过程，我们开始探索被气溶胶感染的小鼠的细胞运动。直到感染后近48小时，当病毒复制达到顶点时，我们才在动物身上检测到任何炎症反应。在这一点上，突然快速产生的趋化因子和细胞因子，我们称之为炎症爆发发生在肺部。细胞因子和趋化因子在血清中达到高水平。远端淋巴细胞室的细胞，特别是骨髓细胞，开始表达干扰素信号，其特征是抗病毒基因的上调。我们的数据表明，骨髓来源的单核细胞迁移到引流淋巴结并参与先天免疫和适应性免疫。我们假设，预激活允许细胞强烈反应并克服病毒NS1蛋白的拮抗作用，导致它们随后迁移到引流淋巴结，在那里它们刺激T细胞活化。

Influenza virus causes a respiratory infection that leads to morbidity and mortality worldwide. The virus infects the respiratory epithelium and replicates rapidly to peak levels in two days. It is eventually cleared from the lungs by a strong cellular immune response. In humans and mice, influenza virus triggers a strong cellular response. Surprisingly influenza virus is a very poor stimulator of DC maturation in vitro because the viral NS1 protein inhibits the maturation process. However, if the DCs are pre-exposed to interferon, the cells can overcome the viral antagonism and respond strongly. To try to better understand the process by which immunity is generated in vivo, we began to explore the cellular movements that occurred in mice infected by aerosol. We were unable to detect any inflammatory response in the animals until almost 48 hours after infection when virus replication was reaching its apex. At this point, a sudden rapid generation of chemokines and cytokines that we refer to as the inflammatory burst occurs in the lungs. Cytokines and chemokines reach high levels in the serum. Cells in distal lymphoid compartments, particularly the bone marrow, begin to express an interferon signature characterized by the up-regulation of antiviral genes. Our data suggests that the bone marrow derived monocytes migrate to the draining lymph nodes and participate in both innate and adaptive immunity. We hypothesize that the preactivation allows the cells to respond strongly and overcome the antagonism of the viral NS1 protein leading to their subsequent migration to the draining lymph nodes where they stimulate T cell activation. In this application we will test the tenets of this hypothesis by studying the events that occur in the lungs during influenza virus infection. A kinetic analysis of chemokine/cytokine/growth factor release will be performed to determine the exact timing and sequence of events that occur during the inflammatory burst in influenza virus infected mice. The effect of inoculum size on the kinetics will be evaluated based upon evidence that suggests an altered kinetics and severity of response in such situations. The cell populations responsible for initiating the inflammatory burst will be identified by the collection of lungs at time points after infection and using a number of sensitive methods to isolate purified populations and probe for the production of inflammatory substances. In Aim 2 we will study the preactivation of monocytes in the bone marrow. Using a PCR panel we will determine if they express an interferon signature and how this may affect their sensitivity to infection, response to virus challenge, and their ability to present antigen to T cells. Finally, a microarray analysis of the bone marrow compartment using mice competent or incompetent to respond to interferon signaling during influenza virus infection will be performed to more comprehensively map the activation profile of the bone marrow. This will allow us to observe both the interferon dependent and independent activation that occurs in the bone marrow during virus infection.