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Complement Resistance Acquired During Acute to Persistent Rubulavirus Infection

急性至持续性风疹病毒感染期间获得的补体耐药性

基本信息

批准号：
10645486
负责人：
Griffith D. Parks
金额：
$ 24.12万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-23 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645486
关键词：
Acute Air Binding Biochemical Biological Assay Cell Culture Techniques Cell Line Cell Survival Cells Clinical Clinical Trials Complement Complement Factor H Complement Inactivators Cytolysis Data Drug Modulation Engineering Environment Epithelial Cells Fibrinogen Future Genetic Polymorphism Genome Goals Human In Vitro Infection Inflammation Innate Immune System Liquid substance Lung Lung infections Mediating Mumps virus Paramyxovirus Pathway interactions Population Production Proteomics RNA Virus Infections Resistance Respiratory System Respiratory Tract Infections Role Rubulavirus Rubulavirus Infections Severities Surface Testing Therapeutic Time Trachea Variant Viral Viral Respiratory Tract Infection Virion Virus Virus Diseases Virus Replication Vitronectin Work acute infection chronic infection conditioning gene complementation inhibitor innate immune mechanisms innate immune pathways interest parainfluenza virus pathogen prototype recruit respiratory respiratory infection virus response sulfated glycoprotein 2 transcriptomics

项目摘要

For many RNA virus infections, an initial acute infection can transition to a prolonged or persistent infection, in which infected cells survive and continue to produce progeny virus. Complement (C’) is a powerful innate immune system which can directly lyse virus-infected cells or neutralize virus (1-4), but the role of C’ in controlling persistent respiratory RNA virus infections is not well understood. Given that viruses have mechanisms to block C’-mediated cell lysis, persistent infections can set up a prolonged inflammation cycle – where activated C’ continues to provide damaging inflammation, but viral inhibitory mechanisms block elimination of pathogen and infected cells. This project emerged from our striking findings that during an initial acute infection of human lung cells with the Rubulavirus Parainfluenza virus 5 (PIV5), infected cells are very sensitive to C’-mediated lysis. Importantly however, after transitioning to a persistent infection, PIV5-infected cells are nearly completely resistant to C’ lysis. Our transcriptomics data show that PIV5 acutely infected cells have low level expression of C’ inhibitors, but this shifts to high level expression of cellular C’ inhibitors Factor H, Factor I, Vitronectin and Clusterin in persistently infected cells. Our central hypothesis is that PIV5 persistently infected cells acquire resistance to C’-mediated lysis due to their acquired ability to express high levels of C’ inhibitors Factor H and Vitronectin. Our goals are to identify: 1) the mechanisms for acquiring C’ resistance during the PIV5 acute-to-persistent transition (Aim 1), and 2) consequences of this shift for production of C’-resistant virus (Aim 2). Aim 1 will define the mechanism for differential sensitivity of airway cells to C’-mediated lysis during transition from acute to persistent infection. Engineered respiratory tract cell lines and primary tracheal or bronchial air-liquid interface (ALI) cell cultures will be used to test the hypothesis that synthesis of C’ inhibitors Factor H and Vitronectin by persistently infected cells results in conditioning of the cells to be resistant to C’-mediated lysis. Aim 2 will identify C’ factors associated with virus particles derived from acute versus persistently infected cells and define the sensitivity of persistent virus to C’- mediated neutralization. Proteomics and biochemical assays will test the hypothesis that virus derived from persistently infected cells will be C’-resistant due to recruitment of Factor H or Vitronectin. Results from our work on C’ interactions with persistent RNA virus infections will have strong potential to inform therapeutics, given: 1) the clinical impact of prolonged viral respiratory infections, 2) polymorphisms in C’ genes can correlate with severity of viral infections, and 3) clinical trials for respiratory tract infections are underway with drugs that modulate C’ responses.

对于许多RNA病毒感染，最初的急性感染可以转变为长期或持续性感染