HMPV/RSV co-infection: effects on replication and viral spread

HMPV/RSV 混合感染：对复制和病毒传播的影响

• 批准号: 10743651
• 负责人: Rebecca E. Dutch
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743651
• 关键词: Affect; Area; Binding; Body Size; Cells; Clinical; Complex; Disease; Event; Filament; Fluorescent in Situ Hybridization; Foundations; Genetic Materials; Genetic Transcription; Genome; Genomics; Glycoproteins; Human; Human Metapneumovirus; Hybrids; Immunocompromised Host; Inclusion Bodies; Individual; Infection; Influenza; Innate Immune Response; Joints; Life Cycle Stages; Location; Messenger RNA; Molecular; Morbidity - disease rate; Natural Immunity; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Physiological; Pneumovirus; Pneumovirus Infections; Proteins; Public Health; Reagent; Reporting; Research; Resources; Respiratory System; Respiratory Tract Infections; Respiratory syncytial virus; Role; Severities; Site; Symptoms; System; Techniques; Testing; Time; Viral; Viral Interference; Virion; Virus; Virus Diseases; Virus Replication; Work; co-infection; experimental study; genetic element; influenzavirus; insight; joint formation; mathematical model; mortality; neutralizing antibody; new therapeutic target; novel; older patient; particle; pathogen; pathogenic virus; pediatric patients; receptor binding; respiratory examination; respiratory infection virus; respiratory virus; single cell technology; superresolution microscopy; viral RNA

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are important respiratory viruses which cause significant morbidity and mortality, particularly in pediatric, elderly and immunocompromised patients. Sensitive molecular techniques show that patients with respiratory infections are frequently infected with more than one viral pathogen. In the case of RSV and HMPV co-infections, while some studies found no or limited impact of co-infection, other research strongly indicates that RSV-HMPV co-infection has a deleterious effect on the course of disease and severity of symptoms. However, few studies have examined the molecular details of co-infection by these two important pathogens. Thus, the impact of RSV/HMPV co-infections remains a critical area for continued study, but relatively little is known about the mechanisms by which co-infections may affect the steps of the viral lifecycle. Viral interference through triggering of innate immunity and also competition for cellular resources have been studied for their roles in co-infection, and very recent work suggests that hybrid viral particles can form between influenza and RSV. Our preliminary studies of HMPV/RSV co-infection demonstrate that inclusion bodies (IBs), which are key regions for viral transcription and replication, can contain both RSV and HMPV genomes in co-infected cells, indicating a shared replication compartment. Our overall hypothesis is that HMPV/RSV co-infection affects both virus replication and virus spread. To test this, we will pursue two Specific Aims, using a range of experimental approaches and the wealth of reagents we have created for the examination of pneumovirus infection. First, we will dissect the effect of HMPV/RSV co-infection on IB formation, dynamics and viral replication, including careful analysis of IBs over the course of infection and analysis of viral transcription and replication at the global and single cell level. Second, we will determine the effect of HMPV/RSV co-infection on potential formation of functional hybrid virus particles. In addition, we will examine whether a unique pathway for cell-to-cell spread which we have characterized for HMPV is also utilized by RSV during co-infection. These important experiments will elucidate new molecular consequences of viral co- infection, providing insight that may inform studies of additional respiratory viruses and lead to new ways to target respiratory virus infections.

呼吸综合病毒（RSV）和人元病毒（HMPV）是重要的呼吸道病毒 引起明显的发病率和死亡率，特别是在小儿，老年和免疫功能低下的患者中。 敏感的分子技术表明，呼吸道感染的患者经常感染更多 比一种病毒病原体。在RSV和HMPV共同感染的情况下，而某些研究没有发现或有限 共同感染的影响，其他研究强烈表明RSV-HMPV共同感染对 疾病和症状的严重程度。但是，很少有研究检查的分子细节 这两种重要病原体共同感染。因此，RSV/HMPV共同感染的影响仍然是关键 继续研究的区域，但对共同感染可能影响的机制知之甚少 病毒生命周期的步骤。通过触发先天免疫和竞争，病毒干扰 已经研究了蜂窝资源在共同感染中的作用，最近的工作表明混合动力 病毒颗粒可以在流感和RSV之间形成。我们对HMPV/RSV共感染的初步研究 证明包容体（IB）是病毒转录和复制的关键区域，可以包含 共同感染的细胞中的RSV和HMPV基因组都表明共享复制区。我们的整体 假设是HMPV/RSV共感染会影响病毒复制和病毒扩散。为了测试这一点，我们将 使用一系列实验方法和我们创造的大量试剂追求两个特定的目标 检查肺炎病毒感染。首先，我们将剖析HMPV/RSV共感染对IB的影响 形成，动力学和病毒复制，包括在感染过程中对IB的仔细分析和 在全球和单细胞水平上分析病毒转录和复制。第二，我们将确定 HMPV/RSV共感染对功能杂交病毒颗粒的潜在形成的影响。此外，我们将 检查是否还利用了我们为HMPV表征的独特的细胞间传播途径 通过共同感染期间的RSV。这些重要的实验将阐明病毒共同的新分子后果 感染，提供可能为其他呼吸道病毒研究提供信息的见解，并导致新方法 靶向呼吸道病毒感染。