NK and T Cell Control of Cowpox Virus

该项目涉及牛痘病毒(CPXV)的免疫控制，它是医学上重要的正痘病毒属的成员。CPXV引起人畜共患感染，在啮齿动物种群中流行，并拥有最大的免疫逃避基因库。该项目基于申请者实验室在CD8T和自然杀伤(NK)细胞控制小鼠CPXV感染方面的已发表工作和初步数据。申请人的实验室显示，CPXV编码两个开放阅读框架(ORF)，抑制感染细胞上主要组织相容性复合体(MHC)I类(MHC-I)的表达。由于CD8 T细胞控制，这些ORF的缺失导致CPXV毒力减弱，这是病毒MHC-I抑制在体内感染中作用的第一个明确例子。T细胞的启动不受影响，但病毒特异性CD8T细胞效应反应被MHC-I抑制而被阻断，这为进一步研究病毒特异性CD8T细胞反应提供了机会。此外，申请人的实验室显示，在CPXV感染后，NK细胞被招募到引流的LN。他们表明，这依赖于干扰素-γ，它诱导表达趋化因子CXCL9、CXCL10和CXCR3的NK细胞。然而，自然杀伤细胞被CPXV抑制产生干扰素-γ。在这个项目中，他们计划解决以下具体目标来进一步研究：1)CD8 T细胞对CPXV的反应；2)CPXV依赖的NK细胞的招募；以及3)新的。具有免疫调节作用的CPXV ORF。正在进行和计划中的实验将在这一U19申请中与其他主要研究人员合作进行。此外，还计划进行人体过渡研究。因此，这些研究将为先天和获得性免疫系统如何控制病毒，如CPXV提供新的见解。

This project deals with immune control of cowpox virus (CPXV), a member ofthe medically important orthopoxvirus genus. CPXV causes zoonotic infections, is endemic in rodent populations, and has the largest repertoire of immune evasion genes. The project is based on published work and preliminary data from the applicant's laboratory on CD8+ T and natural killer (NK) cell control of CPXV infections in mice. The applicant's laboratory showed that CPXV encodes two open reading frames (ORFs) that inhibit major histocompatibility complex (MHC) class I (MHC-I) expression on infected cells. Deletion of these ORFs resulted in attenuated CPXV virulence due to CD8+ T cell control, the first clear-cut example of the role of viral MHC-I inhibition in in vivo infections. T cell priming is not affected but virus-specific CD8+ T cell effector responses are blocked by MHC-I inhibition, providing opportunities for further study of virus-specific CD8+ T cell responses. In addition, the applicant's lab showed that NK cells are recruited to the draining LN following CPXV infection. They showed this was dependent on interferon-gamma which induces the chemokines CXCL9 and CXCL10 and CXCR3-expressing NK cells. However, NK cells are inhibited by CPXV from producing interferon-gamma. In this project, they plan to address the following Specific Aims to further study: 1) CD8+ T cell responses to CPXV; 2) CPXV-dependent recruitment of NK cells; and 3) Novel . immunomodulatory CPXV ORFs. Ongoing and planned experiments will be done in collaboration with other principal investigators in this U19 application. In addition, human transiational studies are planned. Thus, these studies will provide new insight into how the innate and adaptive immune systems control viruses, such as CPXV.