Benjamin R tenOever, PhD

• 2013
  American Society of Virology Ann Palmenberg Award
  

• 2012
  American Society of Gene and Cell Therapy Young Investigator Award
  

• 2012
  Vilcek Award for Creative Promise
  

• 2011
  Cozzarelli Prize Recipient in Biomedical Sciences
  

• 2011
  Investigator in the Pathogenesis of Infectious Diseases
  

• 2010
  Young Investigator Award
  

• 2009
  Milstein Young Investigator Award
  

• 2008
  Presidential Early Career Award for Scientists and Engineers (PECASE)
  

• 2008
  Pew Scholar
  

Specific Clinical/Research Interests: Host-Pathogen Interactions

Current Students: Asiel Benitez, Lauren Aguado, Paul Leon

Postdoctoral Fellows: Sonja Schmid, Ryan Langlois, Simone Backes, Andrew Varble

Research Personnel: Maryline Panis, Jaehee Shim, Ismarc Ryes

Overview:
The tenOever lab broadly focuses on the molecular interactions between viruses and their host. More specifically, the lab studies how the cell responds to virus. This research encompasses the study of cellular antiviral proteins and small RNAs, of both cellular and virus origin, which contribute to the outcome of infection. The overall objective of this lab is to gain a thorough understanding of the molecular basis of virus pathogenicity in an effort to generate improved vaccines and therapeutics.

Summary of Research Studies:
We focus on the interplay between RNA viruses and small RNAs.  This research includes the study of microRNAs and virus-derived small RNAs and their role, if any, in the cellular response to infection.  In addition, we exploit the small RNA machinery of the cell to control virus tropism, virus synthesis of miRNAs, and the biology of virus-derived small RNAs.  Our laboratory uses several techniques to study these RNA-based host-virus interactions including genetic manipulation of both host and pathogen. We are presently working in the following areas.

 

The cellular response to RNA virus infections: Following viral recognition, the cell responds with the secretion of Type I interferon (IFN-I). This is largely coordinated by cellular kinases which mediate the activation of a number of transcription factors. These transcription factors assemble into a multisubunit complex called the enhanceosome to induce IFN-I transcription. The result of IFN-I signaling is the upregulation of a wide variety of interferon stimulated genes (ISGs).  This cellular response functions to render cells resistant to viral infection. We study two kinases critical in the induction and signaling of IFN-I through the genetic manipulation of mice and subsequent in vivo virus infections.

Exploiting microRNAs to control virus tropism: We developed a technology whereby viruses can be engineered to be susceptible to host cell miRNAs.  As miRNAs can demonstrate cell- and/or species-specificity, we can use miRNA-mediated targeting to control virus tropism or the level of replication.   We use this technology to address fundamental questions about immunology as well develop novel virus vaccines.

The biology of influenza A virus small viral RNAs (svRNA): As a result of miRNA profiling in virus infected cells, we serendipitously discovered a small RNA produced by influenza A virus.  While not a miRNA, this small viral RNA (svRNA) accumulates to >10000 copies per cell and has a significant impact on the virus’ replicative cycle.  This area of research presently focuses on the biogenesis and molecular function of svRNA.

Non-canononical cytoplasmic production of viral miRNAs:  We recently determined that viruses could be engineered to produce functional microRNAs.  While this was not surprising for viruses such as influenza A virus, which replicates in the nucleus, we also found cytoplasmic viruses were capable of miRNA synthesis.  This research focus is aimed at determining the molecular basis underlying this phenomenon.

Perez JT, Pham AM, Lorini MH, Chua MA, Steel J, tenOever BR. MicroRNA-Mediated Species-Specific Attenuation of Influenza A Virus. Nat Biotechnol 2009 Jun; 27(6): 572-576.

Perez JT, Varble A, Sachidanandam R, Zlatev I, Manoharan M, García-Sastre A, tenOever BR. Influenza A virus-generated small RNAs regulate the switch from transcription to replication. Proceedings of the National Academy of Sciences of the United States of America 2010 Jun; 107(25).

Shapiro JS, Varble A, tenOever BR. Non-Canonical Cytoplasmic Processing of Viral microRNAs. RNA 2010; 16: 2068-74.

Varble A, Chua MA, Perez JT, Manicassamy B, Garcia-Sastre A, tenOever BR. Engineered RNA Viral Synthesis of microRNAs. PNAS 2010; 107(25): 11519-24.

Schmid S, Mordstein M, Kochs G, Garcia-Sastre A, tenOever BR. Transcription Factor Redundancy Ensures Induction of the Antiviral State. JBC 2010; 285(53): 42013-22.

Langlois RA, Shapiro JS, Pham AM, tenOever BR. In vivo delivery of cytoplasmic RNA virus-derived miRNAs. Molecular therapy : the journal of the American Society of Gene Therapy 2012 Feb; 20(2).

Pham AM, Langlois RA, tenOever BR. Replication in cells of hematopoietic origin is necessary for Dengue virus dissemination. PLoS pathogens 2012 Jan; 8(1).

Shapiro JS, Langlois RA, Pham AM, tenOever BR. Evidence for a cytoplasmic microprocessor of pri-miRNAs. RNA (New York, N.Y.) 2012 Jul; 18(7).

Langlois RA, Varble A, Chua MA, García-Sastre A, tenOever BR. Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses. Proceedings of the National Academy of Sciences of the United States of America 2012 Jul; 109(30).

Backes S, Shapiro JS, Sabin LR, Pham AM, Reyes I, Moss B, Cherry S, tenOever BR. Degradation of host microRNAs by poxvirus poly(A) polymerase reveals terminal RNA methylation as a protective antiviral mechanism. Cell host & microbe 2012 Aug; 12(2).

Perez JT, Zlatev I, Aggarwal S, Subramanian S, Sachidanandam R, Kim B, Manoharan M, tenOever BR. A small-RNA enhancer of viral polymerase activity. Journal of virology 2012 Dec; 86(24).

Chua MA, Schmid S, Perez JT, Langlois RA, tenOever BR. Influenza A Virus Utilizes Suboptimal Splicing to Coordinate the Timing of Infection. Cell reports 2013 Jan;.

tenOever BR. RNA viruses and the host microRNA machinery. Nature reviews. Microbiology 2013 Mar; 11(3).

Langlois RA, Albrecht RA, Kimble B, Sutton T, Shapiro JS, Finch C, Angel M, Chua MA, Gonzalez-Reiche AS, Xu K, Perez D, García-Sastre A, tenOever BR. MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies. Nature biotechnology 2013 Sep; 31(9).

Varble A, Benitez AA, Schmid S, Sachs D, Shim JV, Rodriguez-Barrueco R, Panis M, Crumiller M, Silva JM, Sachidanandam R, tenOever BR. An in vivo RNAi screening approach to identify host determinants of virus replication. Cell host & microbe 2013 Sep; 14(3).

Cullen BR, Cherry S, tenOever BR. Is RNA interference a physiologically relevant innate antiviral immune response in mammals?. Cell host & microbe 2013 Oct; 14(4).

Schmid S, Sachs D, tenOever BR. Mitogen-activated Protein Kinase-mediated Licensing of Interferon Regulatory Factor 3/7 Reinforces the Cell Response to Virus. The Journal of biological chemistry 2014 Jan; 289(1).

Schmid S, Zony LC, tenOever BR. A versatile RNA vector for delivery of coding and non-coding RNAs. Journal of Virology 2013 Dec;.