17The emergence of a novel coronavirus, SARS-CoV-2, resulted in a pandemic. Here, we used X-ray 18 structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from 19 SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, 20 and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins 21 known to serve or not serve as receptor allows to define residues important for binding. From the 20 22 amino acids in ACE2 that contact S up to seven can be replaced and ACE2 can still function as the SARS-23CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery 24 of the binding site, while changes of the invariable residues prevent S-binding or infection of the 25 respective animal. Some ACE2 proteins even tolerate the loss or the acquisition of N-glycosylation sites 26 located near the S-interface. Of note, Pigs and dogs, which are not or not effectively infected and have 27 only a few changes in the binding site, exhibit relatively low levels of ACE2 in the respiratory tract. 28Comparison of the RBD of S of SARS-CoV-2 with viruses from Bat-CoV-RaTG13 and Pangolin-CoV 29 revealed that the latter contains only one substitution, whereas the Bat-CoV-RaTG13 exhibits five. 30However, ACE2 of pangolin exhibit seven changes relative to human ACE2, a similar number of 31 substitutions is present in ACE2 of bats, raccoon, and civet suggesting that SARS-CoV-2 may not 32 especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new 33 insight into the receptor usage and animal source/origin of SARS-CoV-2. 34 IMPORTANCE 35 SARS-CoV-2 is threatening people worldwide and there are no drugs or vaccines available to mitigate 36 its spread. The origin of the virus is still unclear and whether pets and livestock can be infected and 37 transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host 38 receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis 39 provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from 40 species known to support SARS-CoV-2 infection tolerate many amino acid changes indicating that the 41 species barrier might be low. An exception are dogs and especially pigs, which, however, revealed 42
H5N1 influenza A virus (IAV) causes severe respiratory diseases and high mortality rates in animals and humans. MicroRNAs are being increasingly studied to evaluate their potential as therapeutic entities to combat viral infection. However, mechanistic studies delineating the roles of microRNAs in regulating host-H5N1 virus interactions remain scarce. Here, we performed microRNA microarray analysis using A549 human lung epithelial cells infected with a highly pathogenic avian influenza virus. The microRNA expression profile of infected cells identified a small number of microRNAs being dysregulated upon H5N1 influenza A virus infection. Of the differentially expressed microRNAs, miR-136 was up-regulated 5-fold and exhibited potent antiviral activity in vitro against H5N1 influenza A virus, as well as vesicular stomatitis virus. On the one hand, 3′-untranslated region (UTR) reporter analysis revealed a miR-136 binding site in the 3′ UTR of IL-6. However, on the other hand, we subsequently determined that miR-136 meanwhile acts as an immune agonist of retinoic acid-inducible gene 1 (RIG-I), thereby causing IL-6 and IFN-β accumulation in A549 cells. Overall, this study implicates the dual role of miRNA-136 in the regulation of host antiviral innate immunity and suggests an important role for the microRNA-activated pathway in viral infection via pattern recognition receptors.
The 2009 pandemic H1N1 influenza virus (pdm/09) is typically mildly virulent in mice. In a previous study, we identified four novel swine isolates of pdm/09 viruses that exhibited high lethality in mice. Comparing the consensus sequences of the PB2 subunit of human isolates of pdm/09 viruses with those of the four swine isolate viruses revealed one consensus mutation: T588I. In this study, we determined that 588T is an amino acid mutation conserved in pdm/09 viruses that was exceedingly rare in previous human influenza isolates. To investigate whether the PB2 with the T5581 mutation (PB2-T558I) has an effect on the increased pathogenicity, we rescued a variant containing PB2-588I (Mex_PB2-588I) in the pdm/09 virus, A/Mexico/4486/ 2009(H1N1), referred to as Mex_WT (where WT is wild type), and characterized the variant in vitro and in vivo. The results indicated that the mutation significantly enhanced polymerase activity in mammalian cells, and the variant exhibited increased growth properties and induced significant weight loss in a mouse model compared to the wild type. We determined that the mutation exacerbated PB2 inhibition of mitochondrial antiviral signaling protein (MAVS)-mediated beta interferon (IFN-) expression, and PB2-588I was observed to bind to MAVS more efficiently than PB2-588T. The variant induced lower levels of host IFN- expression than the WT strain during infection. These findings indicate that the pdm/09 influenza virus has increased pathogenicity upon the acquisition of the PB2-T588I mutation and highlight the need for the continued surveillance of the genetic variation of molecular markers in influenza viruses because of their potential effects on pathogenicity and threats to human health.
Understanding how infected cells respond to Ebola virus (EBOV) and how this response changes during the process of viral replication and transcription are very important for establishing effective antiviral strategies. In this study, we conducted a genome-wide screen to identify long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and mRNAs differentially expressed during replication and transcription using a tetracistronic transcription and replication-competent virus-like particle (trVLP) system that models the life cycle of EBOV in 293T cells. To characterize the expression patterns of these differentially expressed RNAs, we performed a series cluster analysis, and up- or down-regulated genes were selected to establish a gene co-expression network. Competing endogenous RNA (ceRNA) networks based on the RNAs responsible for the effects induced by EBOV replication and transcription in human cells, including circRNAs, lncRNAs, miRNAs, and mRNAs, were constructed for the first time. Based on these networks, the interaction details of circRNA-chr19 were explored. Our results demonstrated that circRNA-chr19 targeting miR-30b-3p regulated CLDN18 expression by functioning as a ceRNA. These findings may have important implications for further studies of the mechanisms of EBOV replication and transcription. These RNAs potentially have important functions and may be promising targets for EBOV therapy.
Since 2013, highly pathogenic avian influenza H5N6 viruses have emerged in poultry and caused sporadic infections in humans, increasing global concerns regarding their potential as human pandemic threats. Here, we characterized the receptor-binding specificities, pathogenicities and transmissibilities of three H5N6 viruses isolated from poultry in China. The surface genes hemagglutinin (HA) and neuraminidase (NA) were closely related to the human-originating strain A/Changsha/1/2014 (H5N6). Phylogenetic analyses showed that the HA genes were clustered in the 2.3.4.4 clade, and the NA genes were derived from H6N6 viruses. These H5N6 viruses bound both α-2,3-linked and α-2,6-linked sialic acid receptors, but they exhibited different pathogenicities in mice. In addition, one virus was fully infective and transmissible by direct contact in guinea pigs. These results highlight the importance of monitoring the continual adaptation of H5N6 viruses in poultry due to their potential threat to human health.
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