pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production.
pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production.
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pMGF505-7R 通过抑制 IL-1β 和 I 型 IFN 的产生来确定非洲猪瘟病毒感染的致病性
DOI：
10.1371/journal.ppat.1009733
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发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Weng C
中科院分区：
文献类型：
--
作者：
Li J;Song J;Kang L;Huang L;Zhou S;Hu L;Zheng J;Li C;Zhang X;He X;Zhao D;Bu Z;Weng C
炎症因子和I型干扰素（ifn）是宿主抗病毒先天免疫反应的关键成分，可从病原体感染的巨噬细胞中释放出来。非洲猪瘟病毒（ASFV）已经发展出多种策略来逃避宿主的抗病毒先天免疫反应，包括改变炎症反应和干扰素的产生。然而，asfv编码蛋白抑制炎症反应和ifn产生的分子机制尚不完全清楚。在这里，我们报道了ASFV感染仅诱导猪肺泡巨噬细胞（pam）中低水平的IL-1β和I型ifn，即使存在强诱导剂如LPS和poly（dA:dT）。通过进一步探索，我们发现多基因家族360 （MGF360）和MGF505的几个成员强烈抑制IL-1β成熟和IFN-β启动子激活。其中，pMGF505-7R的抑制作用最强。为了验证pMGF505-7R在体内的功能，我们构建并评估了MGF505-7R基因缺失的重组ASFV （ASFV-Δ7R）。正如我们所料，与亲本ASFV HLJ/18株相比，ASFV-Δ7R感染诱导了更高水平的IL-1β和IFN-β。然后发现ASFV感染诱导的IL-1β的产生依赖于TLRs/NF-κB信号通路和NLRP3炎性体。此外，我们发现pMGF505-7R与IKK复合物中的IKKα相互作用，抑制NF-κB的激活，并与NLRP3结合，抑制炎症小体的形成，导致IL-1β的产生减少。此外，我们发现pMGF505-7R与IRF3的核易位相互作用并抑制IRF3的核易位，从而阻断I型IFN的产生。重要的是，与亲本ASFV HLJ/18株相比，ASFV-Δ7R在仔猪中的毒力降低，这可能是由于体内诱导了更高的IL-1β和I型IFN的产生。我们的发现为了解asfv编码pMGF505-7R的功能及其在病毒感染诱导的发病机制中的作用提供了新的线索，这可能有助于设计抗病毒药物或减毒活疫苗来控制ASF。非洲猪瘟病毒（ASFV）引起一种高度致命的猪疾病，目前在许多国家存在，严重影响养猪业。尽管进行了广泛的研究，但仍然缺乏有效的疫苗和抗病毒策略，并且在病毒感染周期的基础生物学知识方面存在相关空白。在本研究中，我们发现ASFV感染仅诱导猪肺泡巨噬细胞（PAMs）中低水平的IL-1β和I型IFN，并鉴定了多基因家族505 （MGF505）成员pMGF505-7R强烈抑制IL-1β和IFN-β的产生。与亲本ASFV HLJ/18株相比，缺乏MGF505-7R基因的ASFV （ASFV-Δ7R）在仔猪中的毒力降低，并诱导PAMs和猪体内IL-1β和IFN-β的产生增加。我们的研究结果显著增加了我们对asfv编码pMGF505-7R的功能及其在发病机制中的作用的认识，这可能为未来减毒活疫苗和抗病毒策略的研究提供线索。
Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF. African swine fever virus (ASFV) causes a highly lethal swine disease that is currently present in many countries, severely affecting the pig industry. Despite extensive research, effective vaccines and antiviral strategies are still lacking and relevant gaps in knowledge of the fundamental biology of the viral infection cycle exist. In this study, we found that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs) and identified that pMGF505-7R, a member of the multigene family 505 (MGF505), strongly inhibited IL-1β and IFN-β production. ASFV lacking the MGF505-7R gene (ASFV-Δ7R) had reduced virulence in piglets and induced increased IL-1β and IFN-β production in PAMs and pigs compared with its parental ASFV HLJ/18 strain. Our results significantly increase our knowledge to understand functions of ASFV-encoded pMGF505-7R and its roles in pathogenesis, which may shed light on future research on live attenuated vaccines and antiviral strategies.
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DOI：
10.1038/nri2851
发表时间：
2010-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.4
作者：
Aarreberg LD;Wilkins C;Ramos HJ;Green R;Davis MA;Chow K;Gale M Jr
通讯作者：
Gale M Jr
影响因子：
5.4
作者：
Afonso, CL;Piccone, ME;Rock, DL
通讯作者：
Rock, DL
影响因子：
4.1
作者：
GARCIA, R;ALMAZAN, F;RODRIGUEZ, JF
通讯作者：
RODRIGUEZ, JF
影响因子：
2.2
作者：
Ahn, Huijeong;Kim, Jeongeun;Lee, Geun-Shik
通讯作者：
Lee, Geun-Shik