Retroviral Evasion of Immune Response

逆转录病毒逃避免疫反应

• 批准号: 8237357
• 负责人: Tatyana V Golovkina
• 金额: $ 43.21万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237357
• 关键词: Acute; Adoption; Alprostadil; Animal Model; Antibiotics; Antibodies; BALB/cJ Mouse; Betaretrovirus; Blood; CD8B1 gene; Cessation of life; Complex; Data; Dendritic Cells; Development; Ensure; Family; Fc Receptor; Gammaretrovirus; Genes; Germ-Free; HIV; Histocompatibility; Human T-Cell Leukemia Viruses; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunoglobulins; Immunologic Deficiency Syndromes; Immunosuppression; Immunosuppressive Agents; Infection; Interferons; Interleukin-10; Interleukin-6; Intestines; Knock-out; Lipopolysaccharides; Longevity; Lymphocyte; Macroglobulins; Major Histocompatibility Complex; Mediating; Milk; Molecular; Mouse Mammary Tumor Virus; Murine leukemia virus; Mus; Myelogenous; Natural Killer Cells; Neonatal; Newborn Infant; Oral; Organism; Pathway interactions; Pattern; Pattern recognition receptor; Process; Production; Property; Reporting; Retroviridae; Role; Route; Signal Pathway; Signal Transduction; Specific Pathogen Frees; Surface; T-Lymphocyte; TLR4 gene; Toll-like receptors; Viral; Viral Antigens; Virion; Virus; Virus Diseases; Virus Replication; arm; commensal microbes; cytokine; cytotoxic; gastrointestinal; germ free condition; human TLR7 protein; immune clearance; in vivo; intraperitoneal; killer T cell; macrophage; mammary tumor virus; neonatal Fc receptor; novel; offspring; oral tolerance; pathogen; response; toll-like receptor 4; trait; transmission process

DESCRIPTION (provided by applicant): We found that Muse Mammary Tumor Virus, a betaretrovirus spread through the milk, requires commensal microbiota for successful transmission. The virus exploits bacterially-produced lipopolysaccharide to elicit immunosuppressive cytokines and thus, counteract anti-virus immune response. Our studies will uncover the rules of retrovirus-microbiota-host interaction by using genetically defined and germ-free mice. PUBLIC HEALTH RELEVANCE: Most viral pathogens launch acute infections, whereby the virus replicates rapidly and disseminates to another organism prior to immune clearance or death of the host. In contrast, some viruses are able to establish persistent infections through adoption of complex relationships with their hosts and manipulation of a wide array of cellular mechanisms for their own advantage. Even though persistent viruses have evolved distinct mechanisms to enable long-term survival in the host, they all share a common trait-the ability to evade the immune system. These viruses are often transmitted most efficiently through mucosal surfaces rich in microbiota, as in the case of Mouse Mammary Tumor Virus. Here, we find that MMTV, when ingested by newborn mice, stimulates unresponsiveness towards viral antigens. This unresponsiveness alleviates immunity against the virus and allows for its indefinite persistence. This process requires intestinal microbiota, as antibiotic-treated mice or germ-free mice do not transmit infectious virus to their offspring. The MMTV-induced tolerance pathway involves activation of Toll-like receptor 4 by lipopolysaccharide and subsequent IL-6- dependent production of the inhibitory cytokine IL-10. Thus, MMTV has evolved to rely on the interaction with omnipresent microbiota to induce the neonatal oral tolerance pathway delineated in this study. Together, these findings underlie the fundamental importance of commensal microbiota in viral infections. Undoubtedly, similar mechanisms operate upon infection with viruses of different families or other pathogens that spread via the gastrointestinal route, making this application broadly significant. We propose to further investigate the role of innate immune and adaptive responses in retrovirus transmission and expand our studies to another animal model in which retroviral transmission could be both blood borne and oral. The overall objective of this proposal is to identify the adaptive immune mechanisms, which control retroviruses and to define the mechanism by which retroviruses evade these responses.

描述（由申请人提供）：我们发现Muse乳腺肿瘤病毒是一种通过乳汁传播的β逆转录病毒，需要肠道微生物群才能成功传播。该病毒利用细菌产生的脂多糖来引发免疫抑制细胞因子，从而抵消抗病毒免疫应答。我们的研究将揭示逆转录病毒-微生物群-宿主相互作用的规则，通过使用遗传定义和无菌小鼠。 公共卫生关系：大多数病毒病原体发起急性感染，由此病毒快速复制并在宿主免疫清除或死亡之前传播到另一个生物体。相比之下，一些病毒能够通过与宿主的复杂关系以及为自身利益操纵各种细胞机制来建立持续感染。尽管持久性病毒已经进化出独特的机制，使其能够在宿主中长期存活，但它们都有一个共同的特征-逃避免疫系统的能力。这些病毒通常通过富含微生物群的粘膜表面最有效地传播，如小鼠乳腺肿瘤病毒的情况。在这里，我们发现，MMTV，当摄入新生小鼠，刺激对病毒抗原无反应。这种无反应性增强了对病毒的免疫力，并使其无限期持续存在。这一过程需要肠道微生物群，因为驱虫小鼠或无菌小鼠不会将传染性病毒传播给后代。MMT诱导的耐受途径涉及脂多糖激活Toll样受体4，随后产生IL-6依赖性抑制性细胞因子IL-10。因此，MMTV已经发展到依赖于与无所不在的微生物群的相互作用来诱导本研究中描绘的新生儿口服耐受途径。总之，这些发现支持了肠道微生物群在病毒感染中的根本重要性。毫无疑问，类似的机制在感染不同家族的病毒或通过胃肠道途径传播的其他病原体时起作用，使得这种应用具有广泛的意义。 我们建议进一步研究先天免疫和适应性反应在逆转录病毒传播中的作用，并将我们的研究扩展到另一种动物模型，其中逆转录病毒传播可以是血液传播和口服。该提案的总体目标是确定控制逆转录病毒的适应性免疫机制，并定义逆转录病毒逃避这些反应的机制。