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The role of TRIM2 and SIRPA in New World Arenavirus entry

TRIM2 和 SIRPA 在新世界沙粒病毒进入中的作用

基本信息

批准号：
10362439
负责人：
SUSAN R ROSS
金额：
$ 44.11万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-23 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362439
关键词：
2019-nCoV Actins Aerosols Amino Acid Motifs Antiviral Response Antiviral Therapy Apoptosis Arenavirus Arenavirus Infections Argentina Binding Biological Process Blood Platelets C-terminal Cell Culture Techniques Cell Extracts Cell Proliferation Cell Surface Proteins Cell surface Cells Complex Cultured Cells Cytoskeleton Data Disease Ebola Endocytosis Erythrocytes Family Functional disorder Genes Glycoproteins Goals Human Human Pathology Image Immune response Immune system In Vitro Incidence Infection Integration Host Factors Junin virus Knockout Mice Lead Link Lymphocytic choriomeningitis virus Mediating Modeling Mus Mutation Old World Arenaviruses PTPN6 gene PTPNS1 gene Pathogenicity Pathway interactions Patients Phagocytosis Phosphoric Monoester Hydrolases Phosphorylation Primates Process Protein Family Proteins RNA Viruses RNA interference screen Rodent Role Sentinel Signal Transduction Signal Transduction Pathway Small Interfering RNA Specificity Survivors TFRC gene TRIM Motif Tacaribe Complex Viruses Tacaribe virus Testing Therapeutic Intervention Time Tissue Extracts Ubiquitination Vaccines Vesicular stomatitis Indiana virus Viral Viral Hemorrhagic Fevers Virus Virus Diseases Work Zika Virus Zoonoses cell type cellular targeting cytokine experimental study in vivo insight knock-down macrophage member mortality neoplastic cell nervous system disorder novel novel strategies novel therapeutic intervention pathogenic virus prevent receptor therapeutic target therapeutically effective trafficking tumor ubiquitin ligase

项目摘要

New world hemorrhagic fever arenaviruses (NWAs), such as Junín virus, are rodent-transmitted viruses that cause ~30% mortality when they zoonose into humans. The mechanism by the NWAs induce disease is still not certain, although it likely includes induction of high levels of cytokines by infected sentinel cells of the immune system, leading to endothelia and thrombocyte dysfunction and neurological disease. Survivors of Junín infection develop strong humoral immune responses, suggesting that controlling infection at early times post-infection is critical for virus clearance. Although an effective Junín virus vaccine has decreased disease incidence, sporadic cases of this as well as the other known and novel NWAs for which there are no vaccines or effective therapeutics still occur. It is well-established that the clade B pathogenic NWAs bind to transferrin receptor 1 and other receptors on the cell surface, but the steps leading to their entry from an acidic cellular compartment are not well-determined. We recently performed a siRNA screen with pseudotyped viruses bearing a pathogenic Junín glycoprotein with the goal of finding host genes involved in entry that could serve as therapeutic targets. We found that TRIM2, a member of the tripartite motif family that includes well-known members of the host's intrinsic defense against viral infections, limits NWA endocytosis into cells. By probing the TRIM2 interactome for other host proteins that block NWA infection, we discovered that SIRPA, a cell surface protein that inhibits macrophage phagocytosis of tumor and dead cells and erythrocytes, also decreases infection. Importantly, SIRPA, unlike TRIM2, inhibits infection by various human pathogenic viruses that require trafficking to an acidic compartment, including VSV, Zika virus, LCMV and Ebola and SARS-Cov-2 pseudoviruses. Our data suggest that TRIM2 and SIRPA act at the viral entry/internalization step. These finding suggests that there are common mechanisms that regulate virus endocytosis and phagocytosis. We propose here to further investigate the overlap between virus-mediated endocytosis and phagocytosis in vitro, ex vivo and in vivo in three aims that will 1) investigate the overlap in the NWA entry and phagocytosis pathways; 2) determine where TRIM2/SIRPA inhibition of infection occurs; and 3) use TRIM2, SIRPA and other relevant knockout mice to probe the roles of these proteins in cell-type specific and in vivo infection by replication-competent NWAs. In addition to providing mechanistic insight into the entry of NWAs into cells, these studies have the potential of increasing our understanding as to how host factors limit infection and could lead to new approaches to therapeutic intervention.

新世界出血热沙粒病毒（NWAs），如Junín病毒，是啮齿动物传播的