Biology and infection of bats with novel bat influenza viruses

项目摘要 流感大流行是由新出现的新型甲型流感病毒（IAV）引起的， 对特定病毒缺乏免疫力的人群。在显著分歧之后， 鉴定了新的HL 17 NL 10和HL 18 NL 11蝙蝠流感A样病毒（BIALV）的基因组序列， 人们担心它们可能对人类构成重大的溢出威胁，因为 IAV和B型流感病毒与新型BIALV无交叉反应性。为了了解这些新型病毒， 对两种病毒都建立了反向遗传学。结果表明，这些病毒的内部基因是 通过产生含有来自蝙蝠病毒的六个内部基因的嵌合蝙蝠病毒， 来自典型IAV的HA和NA的ORF。研究还表明，携带经典的 IAV M基因通过取代蝙蝠M基因的遗传背景可以拯救嵌合蝙蝠病毒。蝙蝠 已被证明对IAV（通常是H9 N2病毒）呈血清阳性。此外，不同来源的蝙蝠细胞 已经证明，这些物种支持人、猪和禽IAV复制。蝙蝠可能是 暴露于BIALV和IAV，可能会发生重组，产生新的病毒，可以感染其他病毒， 包括人类在内的物种。最近的研究表明，拯救的BIALV可以感染犬和人类细胞。所有 事实表明，新的蝙蝠病毒具有人畜共患病的潜力。然而，人们对这些受体知之甚少。 新病毒，感染和免疫反应，在其自然宿主（蝙蝠），或如何保持它们 并在自然宿主中传播蝙蝠是否会被IAV感染，如果感染了， 这些感染在IAV的生态学中扮演什么样的角色？要理解这些小说， 病毒及其对其他物种包括人类的潜在威胁。牙买加果蝠（Artibeus jamaicensis） 在实验上显示对拯救的野生型HL 18 NL 11病毒敏感。因此有 假设牙买加果蝠可以用作理解新型BIALV的模式生物， 它们对包括人类在内的其他物种的潜在威胁这项建议包括三个具体目标： 确定BIALV在蝙蝠中的感染动力学和向性，以及识别细胞受体; 2）确定 BIALV和经典IAV之间的重配潜力和机制; 3）确定哪种蝙蝠适应 免疫应答对于控制BIALV感染至关重要。该提案的结果将提供新颖的 对新型BIALV的生物学和病毒学的深入了解，揭示了鉴定的病毒序列与 蝙蝠，确定蝙蝠可能在病毒生态中发挥的作用，并解决有关其潜在威胁的问题， 包括人类在内的其他物种，这对流感和蝙蝠免疫研究都很重要。 社区.

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.