Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24.
Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24.
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DOI：
10.3390/v15051075
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发表时间：
2023-04-28
期刊：
影响因子：
--
通讯作者：
Bukreyev A
中科院分区：
文献类型：
--
作者：
Ramanathan P;Tigabu B;Santos RI;Ilinykh PA;Kuzmina N;Vogel OA;Thakur N;Ahmed H;Wu C;Amarasinghe GK;Basler CF;Bukreyev A
埃博拉病毒属的成员在人类中表现出致病性的显著差异，其中埃博拉病毒（EBOV）是最致病的，本迪布焦病毒（BDBV）致病性较低，而雷斯顿病毒（RESTV）已知不会在人类中引起疾病。由埃博拉病毒属成员编码的VP 24蛋白通过与宿主嗜核蛋白α核转运蛋白相互作用阻断I型干扰素（IFN-I）信号传导，可能有助于毒力。先前，我们证明了BDBV VP 24（bVP 24）相对于EBOV VP 24（eVP 24）以较低的亲和力与核转运蛋白α蛋白结合，并且这与IFN-I信号传导的抑制降低相关。我们假设修饰eVP 24-核转运蛋白α界面使其类似于bVP 24将减弱拮抗IFN-1应答的能力。我们产生了一组重组EBOV，其在eVP 24-核转运蛋白α界面中含有单一或组合的点突变。在IFN存在下，大多数病毒似乎在IFN-1感受态769-P和IFN-1缺陷型Vero-E6细胞中减毒。然而，即使在两种细胞系以及U3 A STAT 1敲除细胞中不存在IFN的情况下，R140 A突变体也以降低的水平生长。R140 A突变及其与N135 A突变的组合都大大降低了病毒基因组RNA和mRNA的量，表明这些突变以IFN-1非依赖性减毒方式减毒病毒。此外，我们发现与eVP 24不同，bVP 24不抑制干扰素λ 1（IFN-λ1）、干扰素β（IFN-β）和ISG 15，这可能解释了BDBV相对于EBOV的较低致病性。因此，结合核转运蛋白α的VP 24残基通过IFN-I依赖性和非依赖性机制减弱病毒。
Members of the Ebolavirus genus demonstrate a marked differences in pathogenicity in humans with Ebola (EBOV) being the most pathogenic, Bundibugyo (BDBV) less pathogenic, and Reston (RESTV) is not known to cause a disease in humans. The VP24 protein encoded by members of the Ebolavirus genus blocks type I interferon (IFN-I) signaling through interaction with host karyopherin alpha nuclear transporters, potentially contributing to virulence. Previously, we demonstrated that BDBV VP24 (bVP24) binds with lower affinities to karyopherin alpha proteins relative to EBOV VP24 (eVP24), and this correlated with a reduced inhibition in IFN-I signaling. We hypothesized that modification of eVP24-karyopherin alpha interface to make it similar to bVP24 would attenuate the ability to antagonize IFN-I response. We generated a panel of recombinant EBOVs containing single or combinations of point mutations in the eVP24-karyopherin alpha interface. Most of the viruses appeared to be attenuated in both IFN-I-competent 769-P and IFN-I-deficient Vero-E6 cells in the presence of IFNs. However, the R140A mutant grew at reduced levels even in the absence of IFNs in both cell lines, as well as in U3A STAT1 knockout cells. Both the R140A mutation and its combination with the N135A mutation greatly reduced the amounts of viral genomic RNA and mRNA suggesting that these mutations attenuate the virus in an IFN-I-independent attenuation. Additionally, we found that unlike eVP24, bVP24 does not inhibit interferon lambda 1 (IFN-λ1), interferon beta (IFN-β), and ISG15, which potentially explains the lower pathogenicity of BDBV relative to EBOV. Thus, the VP24 residues binding karyopherin alpha attenuates the virus by IFN-I-dependent and independent mechanisms.
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