Biology and infection of bats with novel bat influenza viruses

蝙蝠新型蝙蝠流感病毒的生物学和感染

• 批准号: 10320280
• 负责人: Wenjun Ma
• 金额: $ 41.93万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-10 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320280
• 关键词: Address; Animal Model; Animals; Antibodies; Avian Influenza A Virus; B-Lymphocytes; Biological Assay; Biology; Canis familiaris; Cells; Cellular Immunity; Chiroptera; Communities; Data; Disease; Dose; Ecology; Evolution; Exposure to; Flow Cytometry; Fruit; Future; Generations; Genes; Genetic; Genome; Health; Hong Kong; Human; Immune response; Immunity; Individual; Infection; Influenza; Influenza A Virus, H9N2 Subtype; Influenza A virus; Influenza B Virus; Interferon Type II; Jamaican; Kinetics; Knowledge; Laboratories; Maintenance; Mediating; Molecular; Open Reading Frames; Play; Population; Predisposition; Public Health; Publishing; Quail; Reassortant Viruses; Research; Research Personnel; Resources; Role; Seroprevalences; Signal Transduction; Supporting Cell; Surface Antigens; Systemic infection; T-Lymphocyte; Testing; Tropism; Vertebral column; Viral; Virus; Virus Diseases; Virus Replication; Virus Shedding; Zoonoses; adaptive immune response; base; cross reactivity; cross-species transmission; experimental study; in vivo; influenzavirus; insight; novel; novel virus; pandemic disease; pandemic influenza; receptor; reverse genetics; seropositive; swine influenza; tissue tropism; tool; transcriptomics; virology

Project Summary Influenza pandemics are caused by emergent novel influenza A viruses (IAVs) that transmit efficiently within human populations lacking preexisting immunity against the specific virus. After the significantly divergent genome sequences of novel HL17NL10 and HL18NL11 bat influenza A-like viruses (BIALVs) were identified, concerns have been raised that they may pose significant spillover threats to humans because antibodies to IAVs and influenza B viruses have no cross-reactivity to novel BIALVs. To understand these novel viruses, reverse genetics was established for both viruses. It was demonstrated that internal genes of these viruses are functional through generation of chimeric bat viruses that contain six internal genes from the bat virus and the ORF of both HA and NA from canonical IAVs. It was also shown that reassortant viruses that carry the classical IAV M gene by replacing the bat M gene in the genetic background of chimeric bat virus can be rescued. Bats have been shown to be seropositive to IAVs, frequently to the H9N2 viruses. Furthermore, bat cells from different species have been demonstrated to support human, swine and avian IAV replication. The bats could have been exposed to both BIALVs and IAVs, and reassortment might occur to generate novel viruses that can infect other species including humans. Recent studies showed that rescued BIALVs can infect canine and human cells. All facts suggest a zoonotic potential of novel bat viruses. However, little is known about the receptors of these novel viruses, infection and immunological responses in their natural hosts (bats), or how they are maintained and transmitted among their natural hosts. Whether bats can be infected by IAVs, and if they are infected, what role in the ecology of IAVs do these infections play? Significant knowledge is needed to understand these novel viruses and their potential threats to other species including humans. Jamaican fruit bats (Artibeus jamaicensis) were shown to be experimentally susceptible to the rescued wild type HL18NL11 virus. Therefore, it is hypothesized that Jamaican fruit bats can be used as a model organism for understanding novel BIALVs and their potential threats to other species including humans. This proposal includes three specific aims: 1) To determine BIALV infection kinetics and tropisms in bats, as well as identify cellular receptors; 2) To determine reassortment potential and mechanisms between BIALVs and classical IAVs; 3) To determine which bat adaptive immune responses are critical to controlling BIALV infection. The results from this proposal will provide novel insights into the biology and virology of novel BIALVs, reveal the association of identified viral sequences with bats, identify roles that bats may play in virus ecology, and address concerns regarding their potential threats to other species including humans, which are important for the both influenza and bat immunity research communities.

项目摘要 流感大流感是由新兴的新型流感病毒（IAV）引起的，这些病毒（IAV）有效地在 人群缺乏针对特定病毒的免疫力。显着分歧之后 鉴定出新型HL17NL10和HL18NL11蝙蝠A-A-a样病毒（BIALVS）的基因组序列。 人们一直担心他们可能对人类构成巨大的溢出威胁，因为 IAVS和流感B病毒对新型BIALV没有交叉反应。要了解这些新型病毒， 两种病毒都建立了反向遗传学。证明这些病毒的内部基因是 通过产生的嵌合蝙蝠病毒功能，其中包含来自蝙蝠病毒的六个内部基因和 来自规范IAV的HA和NA的ORF。还显示出携带经典的重新分类病毒 通过在嵌合蝙蝠病毒的遗传背景中替换BAT M基因，可以营救IAV M基因。蝙蝠 已显示出对IAV的血清阳性，通常是H9N2病毒。此外，来自不同的蝙蝠细胞 已证明物种支持人，猪和鸟类IAV复制。蝙蝠可能是 可能会暴露于BiALV和IAVS，并且可能会出现重新分类，以生成可以感染其他的新型病毒 包括人类在内的物种。最近的研究表明，救出的BIALV可以感染犬和人类细胞。全部 事实暗示了新型BAT病毒的人畜共患潜力。但是，这些受体知之甚少 自然宿主（蝙蝠）中的新型病毒，感染和免疫反应，或如何维持它们 并在其自然寄主中传播。蝙蝠是否可以被IAV感染，如果它们被感染，什么 这些感染在IAV的生态学中的作用是否发挥作用？需要重要的知识来理解这些小说 病毒及其对包括人类在内的其他物种的潜在威胁。牙买加水果蝙蝠（Artibeus Jamaicensis） 被证明在实验上容易受到救出的野生型HL18NL11病毒的影响。因此，是 假设牙买加水果蝙蝠可以用作一种模型生物体，以理解新型的bialvs和 他们对包括人类在内的其他物种的潜在威胁。该建议包括三个具体目标：1） 确定蝙蝠中的BIALV感染动力学和乳化性，并鉴定细胞受体。 2）确定 BIALVS和经典IAV之间的重新分类潜力和机制； 3）确定哪种蝙蝠自适应 免疫反应对于控制BIALV感染至关重要。该提案的结果将提供新颖 对新型BIALV的生物学和病毒学的见解，揭示了已鉴定的病毒序列与 蝙蝠，确定蝙蝠可能在病毒生态学中扮演的角色，并解决有关其潜在威胁的担忧 包括人类在内的其他物种，这对流感和BAT免疫研究都很重要 社区。