Department of Epidemiology
Most of the research in our laboratory has used coronaviruses as models to study the genetics of RNA virus transcription, replication, persistence, and cross species transmission. We have also been using alphavirus vaccine vectors to develop novel candidate vaccines against caliciviruses. Specific areas of interest include:
1. Coronavirus Reverse Genetics and vaccine development.
We have developed infectious cDNAs from two coronaviruses. Specific applications include: a) studying critical cis and trans acting factors that regulate coronavirus subgenomic mRNA synthesis and replication, b) rearranging the coronavirus gene order to study genome evolution and function in coronavirus transcription and replication, c) identification of the minimal coronavirus genome, d) development of coronavirus replicon RNAs and coronavirus replicon particles for vaccine development, e) expression of heterologous genes from coronavirus vaccine vectors for swine and other important species.
2. Norwalk like virus (Calicivirus) vaccine development.
We are using the alphavirus, Venezuelan equine encephalitis virus (VEE), as a vaccine vector for the Norwalk like viruses. Our research encompasses: a) expression of Norwalk and SnowMountain virus capsid proteins from VEE, b) biochemical and immunologic characterization of these recombinant proteins, c) vaccine testing in mice, and d) use a human challenge model to identify immunologic responses associated with protection from NLV reinfection.
3. RNA virus transcription, replication and recombination.
Our laboratory has had a longstanding interest in using genetic approaches to study coronavirus transcription, replication and RNA recombination.
4. RNA virus persistence, cross species transmission and virus-host coevolution.
Our laboratory has studied the mechanism for coronavirus persistence in vitro. This occurs by virus selection for resistant host cells that down regulate the expression of the host receptor needed for coronavirus docking and entry. The emergence of these resistant host cells subsequently selects for the coevolution of virus variants that recognize new receptors for docking and entry. Virus variants evolve with expanded host range through recognition of phylogenetic homologues of the normal coronavirus receptor. Consequently, we are studying the mechanisms of RNA virus-host cell coevolution and virus receptor interactions that regulate virus host range expansion.
Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS (2011). Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol. 8(2):270-9.
Lindesmith LC, Donaldson EF, Baric RS (2011). Norovirus GII.4 strain antigenic variation. J Virol. 85(1):231-42.
Sheahan T, Whitmore A, Long K, Ferris M, Rockx B, Funkhouser W, Donaldson E, Gralinski L, Collier M, Heise M, Davis N, Johnston R, Baric RS (2011). Successful vaccination strategies that protect aged mice from lethal challenge from influenza virus and heterologous severe acute respiratory syndrome coronavirus. J Virol. 85(1):217-30.
LoBue AD, Lindesmith LC, Baric RS (2010). Identification of cross-reactive norovirus CD4+ T cell epitopes. J Virol. 84(17):8530-8.
Rockx B, Donaldson E, Frieman M, Sheahan T, Corti D, Lanzavecchia A, Baric RS (2010). Escape from human monoclonal antibody neutralization affects in vitro and in vivo fitness of severe acute respiratory syndrome coronavirus. J Infect Dis. 201(6):946-55.
Lindesmith LC, Donaldson E, Leon J, Moe CL, Frelinger JA, Johnston RE, Weber DJ, Baric RS (2010). Heterotypic humoral and cellular immune responses following Norwalk virus infection. J Virol. 84(4):1800-15
Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS (2009). Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol. 83(13):6689-705.
LoBue AD, Thompson JM, Lindesmith L, Johnston RE, Baric RS (2009). Alphavirus-adjuvanted norovirus-like particle vaccines: heterologous, humoral, and mucosal immune responses protect against murine norovirus challenge. J Virol. 83(7):3212-27.
Donaldson EF, Sims AC, Baric RS (2008). Systematic assembly and genetic manipulation of the mouse hepatitis virus A59 genome. Methods Mol Biol. 454:293-315.
Donaldson EF, Yount B, Sims AC, Burkett S, Pickles RJ, Baric RS (2008). Systematic assembly of a full-length infectious clone of human coronavirus NL63. J Virol. 82(23):11948-57.
Sheahan T, Rockx B, Donaldson E, Corti D, Baric R (2008). Pathways of cross-species transmission of synthetically reconstructed zoonotic severe acute respiratory syndrome coronavirus. J Virol. 82(17):8721-32.
Lindesmith LC, Donaldson EF, Lobue AD, Cannon JL, Zheng DP, Vinje J, Baric RS (2008). Mechanisms of GII.4 norovirus persistence in human populations. PLoS Med. 5(2):e31.
Rockx B, Corti D, Donaldson E, Sheahan T, Stadler K, Lanzavecchia A, Baric R (2008). Structural basis for potent cross-neutralizing human monoclonal antibody protection against lethal human and zoonotic severe acute respiratory syndrome coronavirus challenge. J Virol. 82(7):3220-35.
Sheahan T, Rockx B, Donaldson E, Sims A, Pickles R, Corti D, Baric R (2008). Mechanisms of zoonotic severe acute respiratory syndrome coronavirus host range expansion in human airway epithelium.
J Virol. 82(5):2274-85.
McRoy WC, Baric RS (2008). Amino acid substitutions in the S2 subunit of mouse hepatitis virus variant V51 encode determinants of host range expansion. J Virol. 82(3):1414-24.
Baric RS (2008). SARS-CoV: lessons for global health. Virus Res.133(1):1-3.
Frieman M, Heise M, Baric R (2008). SARS coronavirus and innate immunity. Virus Res. 133(1):101-12.
Enjuanes L, Dediego ML, Alvarez E, Deming D, Sheahan T, Baric R (2008). Vaccines to prevent severe acute respiratory syndrome coronavirus-induced disease. Virus Res. 133(1):45-62.
Deming DJ, Graham RL, Denison MR, Baric RS (2007). Processing of open reading frame 1a replicase proteins nsp7 to nsp10 in murine hepatitis virus strain A59 replication. J Virol. 81(19):10280-91.
Wathelet MG, Orr M, Frieman MB, Baric RS (2007). Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J Virol. 81(21):11620-33.
Frieman M, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS (2007). Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol. 81(18):9812-24.
Rockx B, Sheahan T, Donaldson E, Harkema J, Sims A, Heise M, Pickles R, Cameron M, Kelvin D, Baric R (2007). Synthetic reconstruction of zoonotic and early human severe acute respiratory syndrome coronavirus isolates that produce fatal disease in aged mice. J Virol. 81(14):7410-23.
Donaldson EF, Graham RL, Sims AC, Denison MR, Baric RS (2007). Analysis of murine hepatitis virus strain A59 temperature-sensitive mutant TS-LA6 suggests that nsp10 plays a critical role in polyprotein processing. J Virol. 81(13):7086-98.
Donaldson EF, Sims AC, Graham RL, Denison MR, Baric RS (2007). Murine hepatitis virus replicase protein nsp10 is a critical regulator of viral RNA synthesis. J Virol. 81(12):6356-68.
Deming D, Sheahan T, Heise M, Yount B, Davis N, Sims A, Suthar M, Harkema J, Whitmore A, Pickles R, West A, Donaldson E, Curtis K, Johnston R, Baric R (2006). Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med. 3(12):e525.
Roberts RS, Yount BL, Sims AC, Baker S, Baric RS (2006). Renilla luciferase as a reporter to assess SARS-CoV mRNA transcription regulation and efficacy of anti-SARS-CoV agents. Adv Exp Med Biol. 581:597-600.
Sheahan T, Deming D, Donaldson E, Pickles R, Baric R (2006). Resurrection of an “extinct” SARS-CoV isolate GD03 from late 2003. Adv Exp Med Biol. 581:547-50.
McRoy WC, Baric RS (2006). Spike gene determinants of mouse hepatitis virus host range expansion. Adv Exp Med Biol. 581:301-4.
Frieman MB, Yount B, Sims AC, Deming DJ, Morrison TE, Sparks J, Denison M, Heise M, Baric RS (2006). SARS coronavirus accessory ORFs encode luxury functions. Adv Exp Med Biol. 581:149-52.
Pekosz A, Schaecher SR, Diamond MS, Fremont DH, Sims AC, Baric RS (2006). Structure, expression, and intracellular localization of the SARS-CoV accessory proteins 7a and 7b. Adv Exp Med Biol. 581:115-20.
Deming DJ, Graham RL, Denison MR, Baric RS (2006). MHV-A59 ORF1a replicase protein nsp7-nsp10 processing in replication. Adv Exp Med Biol. 581:101-4.
Donaldson EF, Sims AC, Deming DJ, Baric RS (2006). Mutational analysis of MHV-A59 replicase protein-nsp10. Adv Exp Med Biol. 581:61-6.
Yount B, Roberts RS, Lindesmith L, Baric RS (2006). Rewiring the severe acute respiratory syndrome coronavirus (SARS-CoV) transcription circuit: engineering a recombination-resistant genome. Proc Natl Acad Sci U S A. 103(33):12546-51.
LoBue AD, Lindesmith L, Yount B, Harrington PR, Thompson JM, Johnston RE, Moe CL, Baric RS (2006). Multivalent norovirus vaccines induce strong mucosal and systemic blocking antibodies against multiple strains. Vaccine. 24(24):5220-34.
Yount B, Roberts RS, Sims AC, Deming D, Frieman MB, Sparks J, Denison MR, Davis N, Baric RS (2005). Severe acute respiratory syndrome coronavirus group-specific open reading frames encode nonessential functions for replication in cell cultures and mice. J Virol. 79(23):14909-22.
Lindesmith L, Moe C, Lependu J, Frelinger JA, Treanor J, Baric RS (2005). Cellular and humoral immunity following Snow Mountain virus challenge. J Virol. 79(5):2900-9.
Department of Microbiology & Immunology
Department of Epidemiology
Center for HIV/STDs and Infectious Disease (CFID)
Lineberger Comprehensive Cancer Center (LCCC)
Program in Molecular Biology and Biotechnology
Biological and Biomedical Sciences Program (BBSP)