Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein

Brindley, Melinda A.; Hunt, Catherine L.; Kondratowicz, Andrew S.; Bowman, J. Beatrice; Sinn, Patrick L.; McCray, Paul B.; Quinn, Kathrina; Weller, Melodie L.; Chiorini, John A.; Maury, Wendy

doi:10.1016/j.virol.2011.04.002

Cited by 114 publications

(111 citation statements)

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“…Other PS recognition receptors include Tyrol3, Axl, and MERTK (TAM family proteins), which indirectly interact with PS through the bridging molecules Gas6 and ProS (36,41,42). Axl has been reported to promote infections by EBOV, MARV, and ZIKV (33,35,42,43). However, the roles of TIM and TAM family proteins in HCV infection have not previously been examined experimentally.…”

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confidence: 99%

TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection

Wang

Qiao

Hou

et al. 2017

J Virol

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Human TIM and TAM family proteins were recently found to serve as phosphatidylserine (PS) receptors which promote infections by many different viruses, including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection by hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7.5 cells remarkably lowered HCV cell attachment and subsequent HCV infection. More significantly, the impairment of HCV infection in the TIM-1 knockout cells could be restored completely by ectopic expression of TIM-1 but not TIM-3 or TIM-4. Additionally, HCV infection and cell attachment were inhibited by PS but not by phosphatidylcholine (PC), demonstrating that TIM-1-mediated enhancement of HCV infection is PS dependent. The exposure of PS on the HCV envelope was confirmed by immunoprecipitation of HCV particles with a PS-specific monoclonal antibody. Collectively, these findings demonstrate that TIM-1 promotes HCV infection by serving as an attachment receptor for binding to PS exposed on the HCV envelope.IMPORTANCE TIM family proteins were recently found to enhance infections by many different viruses, including several members of the Flaviviridae family. However, their importance in HCV infection has not previously been examined experimentally. The TIM family proteins include three members in humans: TIM-1, TIM-3, and TIM-4. The findings derived from our studies demonstrate that TIM-1, but not TIM-3 or TIM-4, promotes HCV infection by functioning as an HCV attachment factor. Knockout of the TIM-1 gene resulted in a remarkable reduction of HCV cell attachment and infection. PS-containing liposomes blocked HCV cell attachment and subsequent HCV infection. HCV particles could also be precipitated with a PS-specific monoclonal antibody. These findings suggest that TIM-1 and its binding ligand, PS, may serve as novel targets for antiviral intervention. KEYWORDS hepatitis C virus, TIM-1, attachment, infection, receptor, TIM-3, TIM-4 H epatitis C virus (HCV) is an enveloped RNA virus containing a 9.6-kb singlestranded RNA genome of positive polarity (1). It is the prototype member of the Hepacivirus genus in the Flaviviridae family (2, 3). The viral RNA genome consists of a long open reading frame (ORF), encoding a single polyprotein, and untranslated regions (UTRs) at both the 5= and 3= ends. Upon translation, the viral polyprotein precursor is cleaved by cellular peptidases and the viral NS2/NS3 metalloprotease and NS3/4A serine protease into 10 individual structural and nonstructural (NS) proteins, designated core (C), envelope proteins 1 and 2 (E1 and E2), p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B (4). The structural proteins C, E1, and E2 are essential for the formation of HCV particles (5). The NS3 to NS5B proteins are the minimal set of viral proteins required for HCV RNA replication, although a...

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confidence: 99%

TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection

Wang

Qiao

Hou

et al. 2017

J Virol

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“…Many of them showed significant homologies at the seed sequences that are considered to be an important specific gene silencing motifs. Figure 3 shows the VP24, VP30, VP35, VP40, and L nucleoproteins that constitute the nucleocapsid, which is crucial in both the transcription and viral replication processes [28][29][30][31][32]. The glycoprotein is located in the lipid membrane of the Ebola virus; this is also the place in the host target cells where receptors that facilitate viral entry are embedded [33,34].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ebola Virus by Anti-Ebola miRNAs in silico

Golkar

Battaria

Pace

et al. 2016

J Infect Dev Ctries

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Introduction: MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate transcriptional and posttranscriptional gene regulation of the organisms. miRNA provides immune defense when the body is faced with challenges intracellular agents. miRNA molecules trigger gene silencing in eukaryotic cells. More than 3,000 different human miRNAs (hsa-miRs) have been identified thus far. During ontogenesis, viral or intracellular parasitic infections, miRNAs are differentially expressed to protect the host from intracellular invaders. In a viral infection context, miRNAs have been connected with the interplay between host and pathogen, and occupy a major role in pathogenesis. Methodology: An in silico approach was used to analyze the four major Ebola Virus genome sequences including the recently characterized Ebola virus responsible for West African epidemic that has killed over 10,000 people. All totaled, 2,543 mature human miRNA sequences were retrieved through an miR-database, and the identification of mature miRNAs were aligned with full length sequences of the four major Ebola viruses via computational tools. Results: We identified 32 miRNAs that exhibited significant inhibitory capacity to block more than one EBV strains. miR-607 showed capacity to quell all four major EBVs. Ten putative miRNAs were found to have near perfect identity at seed sequences with numerous targets of Ebola virus that may completely degrade the viral transcripts. Conclusion: We hypothesize that a miRNA-based vaccine can quell Ebola virus infection. Future approaches will focus on validation of these miRNAs in quelling the Ebola virus to further elucidate their biological functions in primate and other animal models.

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“…The signaling pathways are best characterized for viruses that trigger plasma membrane ruffling and macropinocytosis for endocytic uptake. These include vaccinia virus (VACV), Ebola virus, Kaposi's sarcoma-associated herpesvirus (KSHV), adenovirus and influenza A virus (IAV) (Amstutz et al, 2008;Brindley et al, 2011;Chakraborty et al, 2011;de Vries et al, 2011;Eierhoff et al, 2010;Hunt et al, 2011;Kälin et al, 2010;Meertens et al, 2012;Meier et al, 2002;Mercer and Helenius, 2008;Nanbo et al, 2010;Raghu et al, 2009;Saeed et al, 2010;Schmidt et al, 2011;Shimojima et al, 2006;Valiya Veettil et al, 2010).…”

Section: Signalingmentioning

confidence: 99%

“…It is an important entry pathway for a growing number of predominantly larger viruses, such as poxviruses, filoviruses, IAV, adenovirus and HIV1 (Brindley et al, 2011;Callahan et al, 2003;de Vries et al, 2011;Hunt et al, 2011;Mercer and Helenius, 2008;Nanbo et al, 2010;Saeed et al, 2010;Shimojima et al, 2006). As already mentioned, the process involves the activation of a complex signaling pathway that transiently modifies the dynamics of the actin cytoskeleton.…”

Section: Endocytosismentioning

confidence: 99%