Bates Laboratory for the study of Host:Viral interactions                                             Perelman School of Medicine at the University of Pennsylvania

 

 

 

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Research


Ebolavirus-host cell interactions


Forward genetic screens in human haploid cells


Analysis of the cell-intrinsic immune factor tetherin


 

Analysis of the cell-intrinsic immune factor tetherin

Mammalian cells employ numerous innate cellular mechanisms to inhibit viral replication and spread.  Tetherin, also known as Bst2 or CD317, is an interferon-induced, cellular response factor that was initially found to block release of HIV-1 and other retroviruses from infected cells. Our lab demonstrated that Tetherin functions as a broadly acting antiviral factor by showing that both human and murine Tetherin potently inhibit the release of the filovirus, ebolavirus, from the surface of cells.  Moreover we found that the ebolavirus glycoprotein (GP) antagonized the antiviral effect of human and murine Tetherin and facilitated viral budding.  Additionally, ebolavirus GP could substitute for Vpu to promote HIV-1 virion release from Tetherin-expressing cells demonstrating a common cellular target for these divergent viral proteins. Ebolavirus GP efficiently co-immunoprecipitated with Tetherin suggesting that the viral glycoprotein directly interferes with this host antiviral factor.  However, the mechanism by which ebolavirus impedes Tetherin function is unknown and is one of the areas under active investigation in my lab.

An alignment of Tetherin sequences from various mammals revealed two highly conserved methionine residues in the cytoplasmic tail that could serve as potential translation initiation sites due to a “leaky” Kozak sequence around the upstream AUG codon. Based upon this observation, we identified two species of the Tetherin protein generated by alternative translation initiation. The shorter isoform of Tetherin (s-Tetherin) lacks 12 residues present in the cytoplasmic tail of the longer species (l-Tetherin). Analysis of cellular extracts demonstrates that the two Tetherin isofoms are expressed endogenously at nearly equivalent levels in both cultured cell lines and primary CD4 T-cells and are similarly induced by interferon. However whether the ratio of the isoforms is controlled in other cell types, under different conditions or by viral antagonists of Tetherin remains unknown and is being investigated. Transient expression of murine and macaque tetherin cDNA clones also yields two isoforms. The presence of these isoforms under endogenous conditions in multiple species suggests important biological roles for the newly identified l-and s-Tetherin isoforms. Indeed our analysis demonstrates that the two human isoforms have distinct biological functions. Although both act as antiviral factors to retain budding virions, the s-Tetherin isoform is significantly more resistant to HIV Vpu-mediated antagonism and degradation. Consequently s-Tetherin is a very potent HIV-1 restriction factor. By contrast, we demonstrated that the longer isoform, l-Tetherin, is highly susceptible to Vpu mediated antagonism. Importantly, we determined that l-Tetherin (but not s-Tetherin) activates the immune regulatory transcription factor NF-κB. Currently we are deciphering the role(s) of the two Tetherin isoforms in the global immune response to viral infection and their potential function(s) outside of intrinsic immunity.

News & Events

 


01.30.14

Ken finally updates website!!


01.30.14

Press release for MJ & Ken's paper!!


12.18.13

MJ & Ken's paper published in PLoS Pathogens!!


06.07.13

Ben Dyer joins the lab for his thesis work! Did I mention he also received an NSF award?! Go Ben!!


05.31.13

MJ Drake completes her prelim exam!


05.16.13

Alexa Nicolas graduates Penn & completes her thesis work!


05.4.13

Ken Briley presents a poster at the 2013 Viruses & Cells Gordon Conference....in Italia!


09.27.12

Luis Cocka publishes his Tetherin work in PLoS Pathogens!


 


 

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