43 results on '"Stark, Thomas J."'
Search Results
2. SARS-CoV-2 spike D614G change enhances replication and transmission
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Zhou, Bin, Thao, Tran Thi Nhu, Hoffmann, Donata, Taddeo, Adriano, Ebert, Nadine, Labroussaa, Fabien, Pohlmann, Anne, King, Jacqueline, Steiner, Silvio, Kelly, Jenna N., Portmann, Jasmine, Halwe, Nico Joel, Ulrich, Lorenz, Trüeb, Bettina Salome, Fan, Xiaoyu, Hoffmann, Bernd, Wang, Li, Thomann, Lisa, Lin, Xudong, Stalder, Hanspeter, Pozzi, Berta, de Brot, Simone, Jiang, Nannan, Cui, Dan, Hossain, Jaber, Wilson, Malania M., Keller, Matthew W., Stark, Thomas J., Barnes, John R., Dijkman, Ronald, Jores, Joerg, Benarafa, Charaf, Wentworth, David E., Thiel, Volker, and Beer, Martin
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- 2021
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3. RNA-binding protein CPEB1 remodels host and viral RNA landscapes
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Batra, Ranjan, Stark, Thomas J, Clark, Alex E, Belzile, Jean-Philippe, Wheeler, Emily C, Yee, Brian A, Huang, Hui, Gelboin-Burkhart, Chelsea, Huelga, Stephanie C, Aigner, Stefan, Roberts, Brett T, Bos, Tomas J, Sathe, Shashank, Donohue, John Paul, Rigo, Frank, Ares, Manuel, Spector, Deborah H, and Yeo, Gene W
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Biological Sciences ,Bioinformatics and Computational Biology ,Infection ,Generic health relevance ,3' Untranslated Regions ,Alternative Splicing ,Cell Line ,Cytomegalovirus ,Cytomegalovirus Infections ,Gene Expression Regulation ,Host-Pathogen Interactions ,Humans ,Polyadenylation ,RNA ,Messenger ,RNA ,Viral ,Transcription Factors ,Transcriptome ,Up-Regulation ,mRNA Cleavage and Polyadenylation Factors ,Chemical Sciences ,Medical and Health Sciences ,Biophysics ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
Host and virus interactions occurring at the post-transcriptional level are critical for infection but remain poorly understood. Here, we performed comprehensive transcriptome-wide analyses revealing that human cytomegalovirus (HCMV) infection results in widespread alternative splicing (AS), shortening of 3' untranslated regions (3' UTRs) and lengthening of poly(A)-tails in host gene transcripts. We found that the host RNA-binding protein CPEB1 was highly induced after infection, and ectopic expression of CPEB1 in noninfected cells recapitulated infection-related post-transcriptional changes. CPEB1 was also required for poly(A)-tail lengthening of viral RNAs important for productive infection. Strikingly, depletion of CPEB1 reversed infection-related cytopathology and post-transcriptional changes, and decreased productive HCMV titers. Host RNA processing was also altered in herpes simplex virus-2 (HSV-2)-infected cells, thereby indicating that this phenomenon might be a common occurrence during herpesvirus infections. We anticipate that our work may serve as a starting point for therapeutic targeting of host RNA-binding proteins in herpesvirus infections.
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- 2016
4. Comparison of nucleic acid extraction methods for next-generation sequencing of avian influenza A virus from ferret respiratory samples
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Di, Han, Thor, Sharmi W., Trujillo, A. Angelica, Stark, Thomas J., Marinova-Petkova, Atanaska, Jones, Joyce, Wentworth, David E., Barnes, John R., and Davis, C. Todd
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- 2019
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5. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges
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Lovci, Michael T, Ghanem, Dana, Marr, Henry, Arnold, Justin, Gee, Sherry, Parra, Marilyn, Liang, Tiffany Y, Stark, Thomas J, Gehman, Lauren T, Hoon, Shawn, Massirer, Katlin B, Pratt, Gabriel A, Black, Douglas L, Gray, Joe W, Conboy, John G, and Yeo, Gene W
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Health Disparities ,Minority Health ,Human Genome ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Alternative Splicing ,Animals ,Base Pairing ,Base Sequence ,Binding Sites ,Cell Line ,Conserved Sequence ,Humans ,Kinesins ,Mice ,Microfilament Proteins ,Models ,Genetic ,Nucleic Acid Conformation ,RNA Splicing Factors ,RNA ,Messenger ,RNA-Binding Proteins ,Regulatory Sequences ,Ribonucleic Acid ,Chemical Sciences ,Medical and Health Sciences ,Biophysics ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
Alternative splicing (AS) enables programmed diversity of gene expression across tissues and development. We show here that binding in distal intronic regions (>500 nucleotides (nt) from any exon) by Rbfox splicing factors important in development is extensive and is an active mode of splicing regulation. Similarly to exon-proximal sites, distal sites contain evolutionarily conserved GCATG sequences and are associated with AS activation and repression upon modulation of Rbfox abundance in human and mouse experimental systems. As a proof of principle, we validated the activity of two specific Rbfox enhancers in KIF21A and ENAH distal introns and showed that a conserved long-range RNA-RNA base-pairing interaction (an RNA bridge) is necessary for Rbfox-mediated exon inclusion in the ENAH gene. Thus we demonstrate a previously unknown RNA-mediated mechanism for AS control by distally bound RNA-binding proteins.
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- 2013
6. Interim Estimates of 2021-22 Seasonal Influenza Vaccine Effectiveness--United States, February 2022
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Chung, Jessie R., Kim, Sara S., Kondor, Rebecca J., Smith, Catherine, Budd, Alicia P., Tartof, Sara Y., Florea, Ana, Talbot, H. Keipp, Grijalva, Carlos G., Wernli, Karen J., Phillips, C. Hallie, Monto, Arnold S., Martin, Emily T., Belongia, Edward A., McLean, Huong Q., Gaglani, Manjusha, Reis, Michael, Geffel, Krissy Moehling, Nowalk, Mary Patricia, DaSilva, Juliana, Keong, Lisa M., Stark, Thomas J., Barnes, John R., Wentworth, David E., Brammer, Lynnette, Burns, Erin, Fry, Alicia M., Patel, Manish M., and Flannery, Brendan
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Medical research ,Medicine, Experimental ,Vaccination ,Influenza vaccines ,Influenza ,Health - Abstract
In the United States, annual vaccination against seasonal influenza is recommended for all persons aged >6 months except when contraindicated (1). Currently available influenza vaccines are designed to protect against [...]
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- 2022
7. Direct RNA Sequencing of the Coding Complete Influenza A Virus Genome
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Keller, Matthew W., Rambo-Martin, Benjamin L., Wilson, Malania M., Ridenour, Callie A., Shepard, Samuel S., Stark, Thomas J., Neuhaus, Elizabeth B., Dugan, Vivien G., Wentworth, David E., and Barnes, John R.
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- 2018
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8. Transcriptome analysis of human cytomegalovirus infection : : From microRNAs to altered trends in host RNA processing
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Stark, Thomas J.
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Academic Dissertations ,UCSD Dissertations, Academic Biology. (Discipline) - Abstract
Human cytomegalovirus (HCMV) is of clinical importance and is the leading viral cause of birth defects. HCMV infections are also problematic for immunocompromised individuals and organ transplant recipients. This virus infects a variety of cell types in vivo, and although laboratory studies have demonstrated that HCMV does not productively infect embryonic stem cells, the main symptoms in newborns constitute defects in early nervous system development. While the HCMV life cycle has been studied extensively in human fibroblasts, our understanding is limited in terms of how different cell types in the host contribute to the overall infection. The HCMV genome not only has the capacity to encode hundreds of protein products, but also itself encodes microRNAs (miRNAs), and these viral miRNAs reach high abundance during the infection. Here, I first describe comprehensive deep-sequencing characterization of both viral and human miRNAs during lytic HCMV infection of primary fibroblasts. In addition to the identification of two new HCMV-encoded miRNAs, my results also include the finding that the genomic cluster of human miRNAs 182/96/183 is highly upregulated by late stages of infection. For the second stage of my HCMV studies, I present analysis of the full RNA transcriptomes of three different primary cell types undergoing infection. This work was initiated to compare infected neural progenitors with other more permissive cell types, namely fibroblasts and endothelial cells. In my comparative transcriptome analysis I uncovered a wealth of new findings related to conserved effects of HCMV infection on host RNA processing patterns. Finally, I report preliminary results from high-throughput chromosome conformation studies, which have suggested the existence of virus-host DNA interactions during HCMV infection
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- 2014
9. SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility
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Jasmine Portmann, Hanspeter Stalder, Trüeb, Bettina, Salome, Malania M. Wilson, Xudong Lin, Ronald Dijkman, Kelly, Jenna, N., Thao, Tran, Thi, Nhu, Barnes, John, R., Xiaoyu Fan, Simone de Brot, Halwe, Nico, Joel, Matthew W. Keller, Berta Pozzi, Wentworth, David, E., Bin Zhou, Bernd Hoffmann, Fabien Labroussaa, Joerg Jores, Nannan Jiang, Silvio Steiner, Lorenz Ulrich, Jaber Hossain, Jacqueline King, Stark, Thomas, J., Dan Cui, Lisa Thomann, Volker Thiel, Martin Beer, Charaf Benarafa, Donata Hoffmann, Anne Pohlmann, Nadine Ebert, Adriano Taddeo, and Li Wang
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Coronavirus disease 2019 (COVID-19) ,In vivo ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Hamster ,Biology ,respiratory system ,Virology ,Bottle neck ,In vitro ,Transmissibility (vibration) ,Nasal airway ,Article - Abstract
During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic1. However, whether the increasing prevalence of the S-614G variant represents a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains elusive. Here, we generated isogenic SARS-CoV-2 variants and demonstrate that the S-614G variant has (i) enhanced binding to human ACE2, (ii) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and (iii) markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro, it provides a real competitive advantage in vivo, particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating.
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- 2020
10. Effect of Antigenic Drift on Influenza Vaccine Effectiveness in the United States—2019–2020
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Tenforde, Mark W, primary, Kondor, Rebecca J Garten, additional, Chung, Jessie R, additional, Zimmerman, Richard K, additional, Nowalk, Mary Patricia, additional, Jackson, Michael L, additional, Jackson, Lisa A, additional, Monto, Arnold S, additional, Martin, Emily T, additional, Belongia, Edward A, additional, McLean, Huong Q, additional, Gaglani, Manjusha, additional, Rao, Arundhati, additional, Kim, Sara S, additional, Stark, Thomas J, additional, Barnes, John R, additional, Wentworth, David E, additional, Patel, Manish M, additional, and Flannery, Brendan, additional
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- 2020
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11. SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility
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Zhou, Bin, primary, Thao, Tran Thi Nhu, additional, Hoffmann, Donata, additional, Taddeo, Adriano, additional, Ebert, Nadine, additional, Labroussaa, Fabien, additional, Pohlmann, Anne, additional, King, Jacqueline, additional, Portmann, Jasmine, additional, Halwe, Nico Joel, additional, Ulrich, Lorenz, additional, Trüeb, Bettina Salome, additional, Kelly, Jenna N., additional, Fan, Xiaoyu, additional, Hoffmann, Bernd, additional, Steiner, Silvio, additional, Wang, Li, additional, Thomann, Lisa, additional, Lin, Xudong, additional, Stalder, Hanspeter, additional, Pozzi, Berta, additional, de Brot, Simone, additional, Jiang, Nannan, additional, Cui, Dan, additional, Hossain, Jaber, additional, Wilson, Malania, additional, Keller, Matthew, additional, Stark, Thomas J., additional, Barnes, John R., additional, Dijkman, Ronald, additional, Jores, Joerg, additional, Benarafa, Charaf, additional, Wentworth, David E., additional, Thiel, Volker, additional, and Beer, Martin, additional
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- 2020
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12. Effect of Antigenic Drift on Influenza Vaccine Effectiveness in the United States—2019–2020.
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Tenforde, Mark W, Kondor, Rebecca J Garten, Chung, Jessie R, Zimmerman, Richard K, Nowalk, Mary Patricia, Jackson, Michael L, Jackson, Lisa A, Monto, Arnold S, Martin, Emily T, Belongia, Edward A, McLean, Huong Q, Gaglani, Manjusha, Rao, Arundhati, Kim, Sara S, Stark, Thomas J, Barnes, John R, Wentworth, David E, Patel, Manish M, and Flannery, Brendan
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INFLUENZA vaccines ,REVERSE transcriptase polymerase chain reaction ,CLINICAL trials ,CONFIDENCE intervals ,TREATMENT effectiveness ,DESCRIPTIVE statistics ,POLYMERASE chain reaction ,INFLUENZA A virus, H1N1 subtype ,PHARMACODYNAMICS - Abstract
Background At the start of the 2019–2020 influenza season, concern arose that circulating B/Victoria viruses of the globally emerging clade V1A.3 were antigenically drifted from the strain included in the vaccine. Intense B/Victoria activity was followed by circulation of genetically diverse A(H1N1)pdm09 viruses that were also antigenically drifted. We measured vaccine effectiveness (VE) in the United States against illness from these emerging viruses. Methods We enrolled outpatients aged ≥6 months with acute respiratory illness at 5 sites. Respiratory specimens were tested for influenza by reverse-transcriptase polymerase chain reaction (RT-PCR). Using the test-negative design, we determined influenza VE by virus subtype/lineage and genetic subclades by comparing odds of vaccination in influenza cases versus test-negative controls. Results Among 8845 enrollees, 2722 (31%) tested positive for influenza, including 1209 (44%) for B/Victoria and 1405 (51%) for A(H1N1)pdm09. Effectiveness against any influenza illness was 39% (95% confidence interval [CI]: 32–44), 45% (95% CI: 37–52) against B/Victoria and 30% (95% CI: 21–39) against A(H1N1)pdm09-associated illness. Vaccination offered no protection against A(H1N1)pdm09 viruses with antigenically drifted clade 6B.1A 183P-5A+156K HA genes (VE 7%; 95% CI: –14 to 23%) which predominated after January. Conclusions Vaccination provided protection against influenza illness, mainly due to infections from B/Victoria viruses. Vaccine protection against illness from A(H1N1)pdm09 was lower than historically observed effectiveness of 40%–60%, due to late-season vaccine mismatch following emergence of antigenically drifted viruses. The effect of drift on vaccine protection is not easy to predict and, even in drifted years, significant protection can be observed. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Spread of Antigenically Drifted Influenza A(H3N2) Viruses and Vaccine Effectiveness in the United States During the 2018–2019 Season
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Flannery, Brendan, primary, Kondor, Rebecca J Garten, primary, Chung, Jessie R, primary, Gaglani, Manjusha, primary, Reis, Michael, primary, Zimmerman, Richard K, primary, Nowalk, Mary Patricia, primary, Jackson, Michael L, primary, Jackson, Lisa A, primary, Monto, Arnold S, primary, Martin, Emily T, primary, Belongia, Edward A, primary, McLean, Huong Q, primary, Kim, Sara S, primary, Blanton, Lenee, primary, Kniss, Krista, primary, Budd, Alicia P, primary, Brammer, Lynnette, primary, Stark, Thomas J, primary, Barnes, John R, primary, Wentworth, David E, primary, Fry, Alicia M, primary, and Patel, Manish, primary
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- 2019
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14. Detection of highly pathogenic avian influenza A(H5N6) viruses in waterfowl in Bangladesh
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Yang, Genyan, primary, Chowdury, Sukanta, additional, Hodges, Erin, additional, Rahman, Mohammed Ziaur, additional, Jang, Yunho, additional, Hossain, Mohammad Enayet, additional, Jones, Joyce, additional, Stark, Thomas J., additional, Di, Han, additional, Cook, Peter W., additional, Ghosh, Sumon, additional, Azziz-Baumgartner, Eduardo, additional, Barnes, John R., additional, Wentworth, David E., additional, Kennedy, Erin, additional, and Davis, C. Todd, additional
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- 2019
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15. Correction for Sun et al., “Risk Assessment of Fifth-Wave H7N9 Influenza A Viruses in Mammalian Models”
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Sun, Xiangjie, primary, Belser, Jessica A., additional, Pappas, Claudia, additional, Pulit-Penaloza, Joanna A., additional, Brock, Nicole, additional, Zeng, Hui, additional, Creager, Hannah M., additional, Le, Shoshona, additional, Wilson, Malania, additional, Lewis, Amanda, additional, Stark, Thomas J., additional, Shieh, Wun-Ju, additional, Barnes, John, additional, Tumpey, Terrence M., additional, and Maines, Taronna R., additional
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- 2019
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16. Risk Assessment of Fifth-Wave H7N9 Influenza A Viruses in Mammalian Models
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Sun, Xiangjie, primary, Belser, Jessica A., additional, Pappas, Claudia, additional, Pulit-Penaloza, Joanna A., additional, Brock, Nicole, additional, Zeng, Hui, additional, Creager, Hannah M., additional, Le, Shoshona, additional, Wilson, Malania, additional, Lewis, Amanda, additional, Stark, Thomas J., additional, Shieh, Wun-Ju, additional, Barnes, John, additional, Tumpey, Terrence M., additional, and Maines, Taronna R., additional
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- 2019
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17. Author Correction: Direct RNA Sequencing of the Coding Complete Influenza A Virus Genome
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Keller, Matthew W., primary, Rambo-Martin, Benjamin L., additional, Wilson, Malania M., additional, Ridenour, Callie A., additional, Shepard, Samuel S., additional, Stark, Thomas J., additional, Neuhaus, Elizabeth B., additional, Dugan, Vivien G., additional, Wentworth, David E., additional, and Barnes, John R., additional
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- 2018
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18. Spread of Antigenically Drifted Influenza A(H3N2) Viruses and Vaccine Effectiveness in the United States During the 2018-2019 Season.
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Flannery, Brendan, Kondor, Rebecca J Garten, Chung, Jessie R, Gaglani, Manjusha, Reis, Michael, Zimmerman, Richard K, Nowalk, Mary Patricia, Jackson, Michael L, Jackson, Lisa A, Monto, Arnold S, Martin, Emily T, Belongia, Edward A, McLean, Huong Q, Kim, Sara S, Blanton, Lenee, Kniss, Krista, Budd, Alicia P, Brammer, Lynnette, Stark, Thomas J, and Barnes, John R
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VACCINE effectiveness ,VIRAL vaccines ,INFLUENZA ,INFLUENZA vaccines ,INFLUENZA viruses - Abstract
Background: Increased illness due to antigenically drifted A(H3N2) clade 3C.3a influenza viruses prompted concerns about vaccine effectiveness (VE) and vaccine strain selection. We used US virologic surveillance and US Influenza Vaccine Effectiveness (Flu VE) Network data to evaluate consequences of this clade.Methods: Distribution of influenza viruses was described using virologic surveillance data. The Flu VE Network enrolled ambulatory care patients aged ≥6 months with acute respiratory illness at 5 sites. Respiratory specimens were tested for influenza by means of reverse-transcriptase polymerase chain reaction and were sequenced. Using a test-negative design, we estimated VE, comparing the odds of influenza among vaccinated versus unvaccinated participants.Results: During the 2018-2019 influenza season, A(H3N2) clade 3C.3a viruses caused an increasing proportion of influenza cases. Among 2763 Flu VE Network case patients, 1325 (48%) were infected with A(H1N1)pdm09 and 1350 (49%) with A(H3N2); clade 3C.3a accounted for 977 (93%) of 1054 sequenced A(H3N2) viruses. VE was 44% (95% confidence interval, 37%-51%) against A(H1N1)pdm09 and 9% (-4% to 20%) against A(H3N2); VE was 5% (-10% to 19%) against A(H3N2) clade 3C.3a viruses.Conclusions: The predominance of A(H3N2) clade 3C.3a viruses during the latter part of the 2018-2019 season was associated with decreased VE, supporting the A(H3N2) vaccine component update for 2019-2020 northern hemisphere influenza vaccines. [ABSTRACT FROM AUTHOR]- Published
- 2020
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19. Antigenically Diverse Swine Origin H1N1 Variant Influenza Viruses Exhibit Differential Ferret Pathogenesis and Transmission Phenotypes
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Pulit-Penaloza, Joanna A., primary, Jones, Joyce, additional, Sun, Xiangjie, additional, Jang, Yunho, additional, Thor, Sharmi, additional, Belser, Jessica A., additional, Zanders, Natosha, additional, Creager, Hannah M., additional, Ridenour, Callie, additional, Wang, Li, additional, Stark, Thomas J., additional, Garten, Rebecca, additional, Chen, Li-Mei, additional, Barnes, John, additional, Tumpey, Terrence M., additional, Wentworth, David E., additional, Maines, Taronna R., additional, and Davis, C. Todd, additional
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- 2018
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20. Tunable Infrared Metasurface on a Soft Polymer Scaffold
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Reeves, Jeremy B., primary, Jayne, Rachael K., additional, Stark, Thomas J., additional, Barrett, Lawrence K., additional, White, Alice E., additional, and Bishop, David J., additional
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- 2018
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21. Direct RNA Sequencing of the Complete Influenza A Virus Genome
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Keller, Matthew W., primary, Rambo-Martin, Benjamin L., additional, Wilson, Malania M., additional, Ridenour, Callie A., additional, Shepard, Samuel S., additional, Stark, Thomas J., additional, Neuhaus, Elizabeth B., additional, Dugan, Vivien G., additional, Wentworth, David E., additional, and Barnes, John R., additional
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- 2018
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22. Dynamic Actuation of Soft 3D Micromechanical Structures Using Micro‐Electromechanical Systems (MEMS)
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Jayne, Rachael K., primary, Stark, Thomas J., additional, Reeves, Jeremy B., additional, Bishop, David J., additional, and White, Alice E., additional
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- 2018
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23. Multiplex Reverse Transcription-PCR for Simultaneous Surveillance of Influenza A and B Viruses
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Zhou, Bin, primary, Deng, Yi-Mo, additional, Barnes, John R., additional, Sessions, October M., additional, Chou, Tsui-Wen, additional, Wilson, Malania, additional, Stark, Thomas J., additional, Volk, Michelle, additional, Spirason, Natalie, additional, Halpin, Rebecca A., additional, Kamaraj, Uma Sangumathi, additional, Ding, Tao, additional, Stockwell, Timothy B., additional, Salvatore, Mirella, additional, Ghedin, Elodie, additional, Barr, Ian G., additional, and Wentworth, David E., additional
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- 2017
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24. An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody protects mice from morbidity without interfering with the development of protective immunity to subsequent homologous challenge
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Wilson, Jason R., primary, Belser, Jessica A., additional, DaSilva, Juliana, additional, Guo, Zhu, additional, Sun, Xiangjie, additional, Gansebom, Shane, additional, Bai, Yaohui, additional, Stark, Thomas J., additional, Chang, Jessie, additional, Carney, Paul, additional, Levine, Min Z., additional, Barnes, John, additional, Stevens, James, additional, Maines, Taronna R., additional, Tumpey, Terrence M., additional, and York, Ian A., additional
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- 2017
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25. Human Cytomegalovirus Infection of Human Embryonic Stem Cell-Derived Primitive Neural Stem Cells Is Restricted at Several Steps but Leads to the Persistence of Viral DNA
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Belzile, Jean-Philippe, primary, Stark, Thomas J., additional, Yeo, Gene W., additional, and Spector, Deborah H., additional
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- 2014
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26. LIN28 Binds Messenger RNAs at GGAGA Motifs and Regulates Splicing Factor Abundance
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Wilbert, Melissa L., primary, Huelga, Stephanie C., additional, Kapeli, Katannya, additional, Stark, Thomas J., additional, Liang, Tiffany Y., additional, Chen, Stella X., additional, Yan, Bernice Y., additional, Nathanson, Jason L., additional, Hutt, Kasey R., additional, Lovci, Michael T., additional, Kazan, Hilal, additional, Vu, Anthony Q., additional, Massirer, Katlin B., additional, Morris, Quaid, additional, Hoon, Shawn, additional, and Yeo, Gene W., additional
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- 2012
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27. Discrete LIN28 binding sites in mature messenger RNA sequences reveals regulation of a network of splicing factors and downstream alternative splicing patterns
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Wilbert, Melissa L, primary, Huelga, Stephanie C, additional, Vu, Anthony Q, additional, Stark, Thomas J, additional, Massirer, Katlin B, additional, Chen, Stella x, additional, Liang, Tiffany Y, additional, and Yeo, Gene W, additional
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- 2012
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28. High-Resolution Profiling and Analysis of Viral and Host Small RNAs during Human Cytomegalovirus Infection
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Stark, Thomas J., primary, Arnold, Justin D., additional, Spector, Deborah H., additional, and Yeo, Gene W., additional
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- 2012
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29. CSN-5, a Component of the COP9 Signalosome Complex, Regulates the Levels of UNC-96 and UNC-98, Two Components of M-lines inCaenorhabditis elegansMuscle
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Miller, Rachel K., primary, Qadota, Hiroshi, additional, Stark, Thomas J., additional, Mercer, Kristina B., additional, Wortham, Tesheka S., additional, Anyanful, Akwasi, additional, and Benian, Guy M., additional
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- 2009
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30. A Novel Protein Phosphatase is a Binding Partner for the Protein Kinase Domains of UNC-89 (Obscurin) inCaenorhabditis elegans
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Qadota, Hiroshi, primary, McGaha, Lee Anne, additional, Mercer, Kristina B., additional, Stark, Thomas J., additional, Ferrara, Tracey M., additional, and Benian, Guy M., additional
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- 2008
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31. CSN-5, a Component of the COP9 Signalosome Complex, Regulates the Levels of UNC-96 and UNC-98, Two Components of M-lines in Caenorhabditis elegansMuscle
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Miller, Rachel K., Qadota, Hiroshi, Stark, Thomas J., Mercer, Kristina B., Wortham, Tesheka S., Anyanful, Akwasi, and Benian, Guy M.
- Abstract
In Caenorhabditis eleganstwo M-line proteins, UNC-98 and UNC-96, are involved in myofibril assembly and/or maintenance, especially myosin thick filaments. We found that CSN-5, a component of the COP9 signalosome complex, binds to UNC-98 and -96 using the yeast two-hybrid method. These interactions were confirmed by biochemical methods. The CSN-5 protein contains a Mov34 domain. Although one other COP9 signalosome component, CSN-6, also has a Mov34 domain, CSN-6 did not interact with UNC-98 or -96. Anti-CSN-5 antibody colocalized with paramyosin at A-bands in wild type and colocalized with abnormal accumulations of paramyosin found in unc-98, -96, and -15(encodes paramyosin) mutants. Double knockdown of csn-5and -6could slightly suppress the unc-96mutant phenotype. In the double knockdown of csn-5and -6, the levels of UNC-98 protein were increased and the levels of UNC-96 protein levels were slightly reduced, suggesting that CSN-5 promotes the degradation of UNC-98 and that CSN-5 stabilizes UNC-96. In unc-15and unc-96mutants, CSN-5 protein was reduced, implying the existence of feed back regulation from myofibril proteins to CSN-5 protein levels. Taken together, we found that CSN-5 functions in muscle cells to regulate UNC-98 and -96, two M-line proteins.
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- 2009
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32. A Novel Protein Phosphatase is a Binding Partner for the Protein Kinase Domains of UNC-89 (Obscurin) in Caenorhabditis elegans
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Qadota, Hiroshi, McGaha, Lee Anne, Mercer, Kristina B., Stark, Thomas J., Ferrara, Tracey M., and Benian, Guy M.
- Abstract
Mutation of the Caenorhabditis elegansgene unc-89results in disorganization of muscle A-bands. unc-89encodes a giant polypeptide (900 kDa) containing two protein kinase domains, PK1 and PK2. Yeast two-hybrid screening using a portion of UNC-89 including PK2, yielded SCPL-1 (small CTD phosphatase-like-1), which contains a C terminal domain (CTD) phosphatase type domain. In addition to the PK2 domain, interaction with SCPL-1 required the putative autoinhibitory sequence, and immunoglobulin (Ig) and fibronectin type 3 (Fn3) domains lying N-terminal of the kinase domain. SCPL-1 also interacts with PK1, and it similarly requires the kinase domain and upstream Fn3 and Ig domains. Analogous regions from the two other giant kinases of C. elegans, twitchin and TTN-1, failed to interact with SCPL-1. The interaction between SCPL-1 and either Ig-Fn3-PK2 or Fn3-Ig-PK1 was confirmed by biochemical methods. The scpl-1bpromoter is expressed in the same set of muscles as unc-89. Antibodies to SCPL-1 localize to the M-line and a portion of the I-band. Bacterially expressed SCPL-1 proteins have phosphatase activity in vitro with properties similar to previously characterized members of the CTD phosphatase family. RNA interference knockdown results in a defect in the function of egg-laying muscles. These studies suggest a new role for the CTD phosphatase family, that is, in muscle giant kinase signaling.
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- 2008
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33. SARS-CoV-2 spike D614G change enhances replication and transmission
- Author
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Zhou, Bin, Tran, Thi Nhu Thao, Hoffmann, Donata, Taddeo, Adriano, Ebert, Nadine, Labroussaa, Fabien, Pohlmann, Anne, King, Jacqueline, Steiner, Silvio, Kelly, Jenna N., Portmann, Jasmine, Halwe, Nico Joel, Ulrich, Lorenz, Trüeb, Bettina Salome, Fan, Xiaoyu, Hoffmann, Bernd, Wang, Li, Thomann, Lisa, Lin, Xudong, Stalder, Hanspeter, Pozzi, Berta, De Brot, Simone, Jiang, Nannan, Cui, Dan, Hossain, Jaber, Wilson, Malania M., Keller, Matthew W., Stark, Thomas J., Barnes, John R., Dijkman, Ronald, Jores, Jörg, Benarafa, Charaf, Wentworth, David E., Thiel, Volker, and Beer, Martin
- Subjects
630 Agriculture ,570 Life sciences ,biology ,610 Medicine & health ,3. Good health - Abstract
During the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic1. However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo-particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating.
34. Stereochemistry and mechanism of a radical-induced (EH) elimination reaction. Reaction of trichloromethyl radicals with 2-(trimethylstannyl)butane and 3-deuterio-2-(trimethylstannyl)butane
- Author
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Stark, Thomas J., primary, Nelson, Norman T., additional, and Jensen, Frederick R., additional
- Published
- 1980
- Full Text
- View/download PDF
35. Free radical cross-linking in the preparation of non-extractable stationay phases for capillary gas chromatography
- Author
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Wright, Bob W., primary, Peaden, A., additional, Lee, Milton L., additional, and Stark, Thomas J., additional
- Published
- 1982
- Full Text
- View/download PDF
36. Separation of C1-C5 Hydrocarbons on Crosslinked Methyl Silicone Fused Silica WCOT Columns
- Author
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Stark, Thomas J. and Larson, Paul A.
- Abstract
The efficiency of separation of C
1 -C5 hydrocarbons on fused silica WCOT columns, coated with conventional adsorbed or crosslinked dimethyl silicone gums, was investigated. The adsorbed phase columns showed dramatic loss of efficiency at -60°C and lower, while the crosslinked columns showed a more gradual loss. At -70°C, ethylene, acetylene, and ethane are sharp, baseline-resolved peaks on the crosslinked column, but are overlapped, shifted, and badly skewed on the adsorbed phase. Temperature-programmed separtion of refinery gas hydrocarbons is possible on either column with a starting temperature of -50°C; but after a 2-min intial hold at 60°C, the adsorbed phase column can no longer fully resolve the mixture. These effects are discussed in terms of glass transition phenomena.- Published
- 1982
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37. Risk Assessment of Fifth-Wave H7N9 Influenza A Viruses in Mammalian Models.
- Author
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Xiangjie Sun, Belser, Jessica A., Pappas, Claudia, Pulit-Penaloza, Joanna A., Brock, Nicole, Hui Zeng, Creager, Hannah M., Shoshona Le, Wilson, Malania, Lewis, Amanda, Stark, Thomas J., Wun-Ju Shieh, Barnes, John, Tumpey, Terrence M., and Maines, Taronna R.
- Subjects
- *
H7N9 Influenza , *INFLUENZA A virus, H7N9 subtype , *AVIAN influenza , *ANIMAL diseases , *RISK assessment , *ANIMAL species - Abstract
The fifth wave of the H7N9 influenza epidemic in China was distinguished by a sudden increase in human infections, an extended geographic distribution, and the emergence of highly pathogenic avian influenza (HPAI) viruses. Genetically, some H7N9 viruses from the fifth wave have acquired novel amino acid changes at positions involved in mammalian adaptation, antigenicity, and hemagglutinin cleavability. Here, several human low-pathogenic avian influenza (LPAI) and HPAI H7N9 virus isolates from the fifth epidemic wave were assessed for their pathogenicity and transmissibility in mammalian models, as well as their ability to replicate in human airway epithelial cells. We found that an LPAI virus exhibited a similar capacity to replicate and cause disease in two animal species as viruses from previous waves. In contrast, HPAI H7N9 viruses possessed enhanced virulence, causing greater lethargy and mortality, with an extended tropism for brain tissues in both ferret and mouse models. These HPAI viruses also showed signs of adaptation to mammalian hosts by acquiring the ability to fuse at a lower pH threshold than other H7N9 viruses. All of the fifth-wave H7N9 viruses were able to transmit among cohoused ferrets but exhibited a limited capacity to transmit by respiratory droplets, and deep sequencing analysis revealed that the H7N9 viruses sampled after transmission showed a reduced amount of minor variants. Taken together, we conclude that the fifth-wave HPAI H7N9 viruses have gained the ability to cause enhanced disease in mammalian models and with further adaptation may acquire the ability to cause an H7N9 pandemic. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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38. Genetic drift and purifying selection shape within-host influenza A virus populations during natural swine infections.
- Author
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VanInsberghe D, McBride DS, DaSilva J, Stark TJ, Lau MSY, Shepard SS, Barnes JR, Bowman AS, Lowen AC, and Koelle K
- Abstract
Patterns of within-host influenza A virus (IAV) diversity and evolution have been described in natural human infections, but these patterns remain poorly characterized in non-human hosts. Elucidating these dynamics is important to better understand IAV biology and the evolutionary processes that govern spillover into humans. Here, we sampled an IAV outbreak in pigs during a week-long county fair to characterize viral diversity and evolution in this important reservoir host. Nasal wipes were collected on a daily basis from all pigs present at the fair, yielding up to 421 samples per day. Subtyping of PCR-positive samples revealed the co-circulation of H1N1 and H3N2 subtype IAVs. PCR-positive samples with robust Ct values were deep-sequenced, yielding 506 sequenced samples from a total of 253 pigs. Based on higher-depth re-sequenced data from a subset of these initially sequenced samples (260 samples from 168 pigs), we characterized patterns of within-host IAV genetic diversity and evolution. We find that IAV genetic diversity in single-subtype infected pigs is low, with the majority of intra-host single nucleotide variants (iSNVs) present at frequencies of <10%. The ratio of the number of nonsynonymous to the number of synonymous iSNVs is significantly lower than under the neutral expectation, indicating that purifying selection shapes patterns of within-host viral diversity in swine. The dynamic turnover of iSNVs and their pronounced frequency changes further indicate that genetic drift also plays an important role in shaping IAV populations within pigs. Taken together, our results highlight similarities in patterns of IAV genetic diversity and evolution between humans and swine, including the role of stochastic processes in shaping within-host IAV dynamics.
- Published
- 2023
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39. Influenza A Virus Multicycle Replication Yields Comparable Viral Population Emergence in Human Respiratory and Ocular Cell Types.
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Kieran TJ, DaSilva J, Stark TJ, York IA, Pappas C, Barnes JR, Maines TR, and Belser JA
- Subjects
- Animals, Humans, Dogs, Respiratory System, Madin Darby Canine Kidney Cells, Influenza A virus genetics, Influenza, Human, Conjunctivitis
- Abstract
While primarily considered a respiratory pathogen, influenza A virus (IAV) is nonetheless capable of spreading to, and replicating in, numerous extrapulmonary tissues in humans. However, within-host assessments of genetic diversity during multicycle replication have been largely limited to respiratory tract tissues and specimens. As selective pressures can vary greatly between anatomical sites, there is a need to examine how measures of viral diversity may vary between influenza viruses exhibiting different tropisms in humans, as well as following influenza virus infection of cells derived from different organ systems. Here, we employed human primary tissue constructs emulative of the human airway or corneal surface, and we infected both with a panel of human- and avian-origin IAV, inclusive of H1 and H3 subtype human viruses and highly pathogenic H5 and H7 subtype viruses, which are associated with both respiratory disease and conjunctivitis following human infection. While both cell types supported productive replication of all viruses, airway-derived tissue constructs elicited greater induction of genes associated with antiviral responses than did corneal-derived constructs. We used next-generation sequencing to examine viral mutations and population diversity, utilizing several metrics. With few exceptions, generally comparable measures of viral diversity and mutational frequency were detected following homologous virus infection of both respiratory-origin and ocular-origin tissue constructs. Expansion of within-host assessments of genetic diversity to include IAV with atypical clinical presentations in humans or in extrapulmonary cell types can provide greater insight into understanding those features most prone to modulation in the context of viral tropism. IMPORTANCE Influenza A virus (IAV) can infect tissues both within and beyond the respiratory tract, leading to extrapulmonary complications, such as conjunctivitis or gastrointestinal disease. Selective pressures governing virus replication and induction of host responses can vary based on the anatomical site of infection, yet studies examining within-host assessments of genetic diversity are typically only conducted in cells derived from the respiratory tract. We examined the contribution of influenza virus tropism on these properties two different ways: by using IAV associated with different tropisms in humans, and by infecting human cell types from two different organ systems susceptible to IAV infection. Despite the diversity of cell types and viruses employed, we observed generally similar measures of viral diversity postinfection across all conditions tested; these findings nonetheless contribute to a greater understanding of the role tissue type contributes to the dynamics of virus evolution within a human host., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
- Full Text
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40. Interim Estimates of 2021-22 Seasonal Influenza Vaccine Effectiveness - United States, February 2022.
- Author
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Chung JR, Kim SS, Kondor RJ, Smith C, Budd AP, Tartof SY, Florea A, Talbot HK, Grijalva CG, Wernli KJ, Phillips CH, Monto AS, Martin ET, Belongia EA, McLean HQ, Gaglani M, Reis M, Geffel KM, Nowalk MP, DaSilva J, Keong LM, Stark TJ, Barnes JR, Wentworth DE, Brammer L, Burns E, Fry AM, Patel MM, and Flannery B
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Humans, Infant, Influenza A Virus, H1N1 Subtype immunology, Influenza B virus immunology, Middle Aged, Population Surveillance, Seasons, United States epidemiology, Vaccination, Influenza A Virus, H3N2 Subtype immunology, Influenza A virus immunology, Influenza Vaccines administration & dosage, Influenza, Human prevention & control, Vaccine Efficacy
- Abstract
In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months except when contraindicated (1). Currently available influenza vaccines are designed to protect against four influenza viruses: A(H1N1)pdm09 (the 2009 pandemic virus), A(H3N2), B/Victoria lineage, and B/Yamagata lineage. Most influenza viruses detected this season have been A(H3N2) (2). With the exception of the 2020-21 season, when data were insufficient to generate an estimate, CDC has estimated the effectiveness of seasonal influenza vaccine at preventing laboratory-confirmed, mild/moderate (outpatient) medically attended acute respiratory infection (ARI) each season since 2004-05. This interim report uses data from 3,636 children and adults with ARI enrolled in the U.S. Influenza Vaccine Effectiveness Network during October 4, 2021-February 12, 2022. Overall, vaccine effectiveness (VE) against medically attended outpatient ARI associated with influenza A(H3N2) virus was 16% (95% CI = -16% to 39%), which is considered not statistically significant. This analysis indicates that influenza vaccination did not reduce the risk for outpatient medically attended illness with influenza A(H3N2) viruses that predominated so far this season. Enrollment was insufficient to generate reliable VE estimates by age group or by type of influenza vaccine product (1). CDC recommends influenza antiviral medications as an adjunct to vaccination; the potential public health benefit of antiviral medications is magnified in the context of reduced influenza VE. CDC routinely recommends that health care providers continue to administer influenza vaccine to persons aged ≥6 months as long as influenza viruses are circulating, even when VE against one virus is reduced, because vaccine can prevent serious outcomes (e.g., hospitalization, intensive care unit (ICU) admission, or death) that are associated with influenza A(H3N2) virus infection and might protect against other influenza viruses that could circulate later in the season., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Ana Florea reports unrelated institutional grant support for research from Gilead, GlaxoSmithKline, Moderna, and Pfizer. Carlos G. Grijalva reports consulting fees from Merck, Pfizer, and Sanofi Pasteur, and institutional grant support from the Agency for Health Care Research and Quality, Campbell Alliance/Syneos Health, the Food and Drug Administration, and the National Institutes of Health. Emily T. Martin reports institutional grant support from Merck. Arnold S. Monto reports personal fees from Sanofi and nonfinancial support from Seqirus. Mary Patricia Nowalk reports unrelated institutional grant support and personal fees from Merck Sharp & Dohme and institutional investigator-initiated grant support from Sanofi Pasteur. Sara Y. Tartof reports unrelated institutional grant support from Pfizer and GlaxoSmithKline. David E. Wentworth reports institutional grant support from Seqirus for a cooperative research and development agreement on isolation and propagation of influenza viruses in qualified manufacturing cell lines and patents 10,030,231 (influenza reassortment) and 10,272,149 (modified bat influenza viruses and their uses). No other potential conflicts of interest were disclosed.
- Published
- 2022
- Full Text
- View/download PDF
41. Genomic Surveillance for SARS-CoV-2 Variants: Predominance of the Delta (B.1.617.2) and Omicron (B.1.1.529) Variants - United States, June 2021-January 2022.
- Author
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Lambrou AS, Shirk P, Steele MK, Paul P, Paden CR, Cadwell B, Reese HE, Aoki Y, Hassell N, Zheng XY, Talarico S, Chen JC, Oberste MS, Batra D, McMullan LK, Halpin AL, Galloway SE, MacCannell DR, Kondor R, Barnes J, MacNeil A, Silk BJ, Dugan VG, Scobie HM, Wentworth DE, Caravas J, Kovacs NA, Gerhart JG, Jia Ng H, Beck A, Chau R, Cintron R, Cook PW, Gulvik CA, Howard D, Jang Y, Knipe K, Lacek KA, Moser KA, Paskey AC, Rambo-Martin BL, Nagilla RR, Retchless AC, Schmerer MW, Seby S, Shepard SS, Stanton RA, Stark TJ, Uehara A, Unoarumhi Y, Bentz ML, Burgin A, Burroughs M, Davis ML, Keller MW, Keong LM, Le SS, Lee JS, Madden Jr JC, Nobles S, Owuor DC, Padilla J, Sheth M, and Wilson MM
- Subjects
- Centers for Disease Control and Prevention, U.S., Genomics, Humans, Prevalence, Public Health Surveillance methods, United States epidemiology, COVID-19 epidemiology, COVID-19 virology, SARS-CoV-2 genetics
- Abstract
Genomic surveillance is a critical tool for tracking emerging variants of SARS-CoV-2 (the virus that causes COVID-19), which can exhibit characteristics that potentially affect public health and clinical interventions, including increased transmissibility, illness severity, and capacity for immune escape. During June 2021-January 2022, CDC expanded genomic surveillance data sources to incorporate sequence data from public repositories to produce weighted estimates of variant proportions at the jurisdiction level and refined analytic methods to enhance the timeliness and accuracy of national and regional variant proportion estimates. These changes also allowed for more comprehensive variant proportion estimation at the jurisdictional level (i.e., U.S. state, district, territory, and freely associated state). The data in this report are a summary of findings of recent proportions of circulating variants that are updated weekly on CDC's COVID Data Tracker website to enable timely public health action.
† The SARS-CoV-2 Delta (B.1.617.2 and AY sublineages) variant rose from 1% to >50% of viral lineages circulating nationally during 8 weeks, from May 1-June 26, 2021. Delta-associated infections remained predominant until being rapidly overtaken by infections associated with the Omicron (B.1.1.529 and BA sublineages) variant in December 2021, when Omicron increased from 1% to >50% of circulating viral lineages during a 2-week period. As of the week ending January 22, 2022, Omicron was estimated to account for 99.2% (95% CI = 99.0%-99.5%) of SARS-CoV-2 infections nationwide, and Delta for 0.7% (95% CI = 0.5%-1.0%). The dynamic landscape of SARS-CoV-2 variants in 2021, including Delta- and Omicron-driven resurgences of SARS-CoV-2 transmission across the United States, underscores the importance of robust genomic surveillance efforts to inform public health planning and practice., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.- Published
- 2022
- Full Text
- View/download PDF
42. SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility.
- Author
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Zhou B, Thao TTN, Hoffmann D, Taddeo A, Ebert N, Labroussaa F, Pohlmann A, King J, Portmann J, Halwe NJ, Ulrich L, Trüeb BS, Kelly JN, Fan X, Hoffmann B, Steiner S, Wang L, Thomann L, Lin X, Stalder H, Pozzi B, de Brot S, Jiang N, Cui D, Hossain J, Wilson M, Keller M, Stark TJ, Barnes JR, Dijkman R, Jores J, Benarafa C, Wentworth DE, Thiel V, and Beer M
- Abstract
During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic
1 . However, whether the increasing prevalence of the S-614G variant represents a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains elusive. Here, we generated isogenic SARS-CoV-2 variants and demonstrate that the S-614G variant has (i) enhanced binding to human ACE2, (ii) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and (iii) markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro , it provides a real competitive advantage in vivo , particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating.- Published
- 2020
- Full Text
- View/download PDF
43. Risk Assessment of Fifth-Wave H7N9 Influenza A Viruses in Mammalian Models.
- Author
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Sun X, Belser JA, Pappas C, Pulit-Penaloza JA, Brock N, Zeng H, Creager HM, Le S, Wilson M, Lewis A, Stark TJ, Shieh WJ, Barnes J, Tumpey TM, and Maines TR
- Subjects
- Animals, Cell Line, China epidemiology, Chlorocebus aethiops, Epidemics, Evolution, Molecular, Ferrets, High-Throughput Nucleotide Sequencing methods, Humans, Influenza A Virus, H7N9 Subtype genetics, Influenza, Human epidemiology, Influenza, Human transmission, Mice, Orthomyxoviridae Infections transmission, Orthomyxoviridae Infections virology, Risk Assessment, Vero Cells, Viral Tropism, Virulence, Influenza A Virus, H7N9 Subtype pathogenicity, Influenza, Human virology, Orthomyxoviridae Infections epidemiology, RNA, Viral genetics, Sequence Analysis, RNA methods
- Abstract
The fifth wave of the H7N9 influenza epidemic in China was distinguished by a sudden increase in human infections, an extended geographic distribution, and the emergence of highly pathogenic avian influenza (HPAI) viruses. Genetically, some H7N9 viruses from the fifth wave have acquired novel amino acid changes at positions involved in mammalian adaptation, antigenicity, and hemagglutinin cleavability. Here, several human low-pathogenic avian influenza (LPAI) and HPAI H7N9 virus isolates from the fifth epidemic wave were assessed for their pathogenicity and transmissibility in mammalian models, as well as their ability to replicate in human airway epithelial cells. We found that an LPAI virus exhibited a similar capacity to replicate and cause disease in two animal species as viruses from previous waves. In contrast, HPAI H7N9 viruses possessed enhanced virulence, causing greater lethargy and mortality, with an extended tropism for brain tissues in both ferret and mouse models. These HPAI viruses also showed signs of adaptation to mammalian hosts by acquiring the ability to fuse at a lower pH threshold than other H7N9 viruses. All of the fifth-wave H7N9 viruses were able to transmit among cohoused ferrets but exhibited a limited capacity to transmit by respiratory droplets, and deep sequencing analysis revealed that the H7N9 viruses sampled after transmission showed a reduced amount of minor variants. Taken together, we conclude that the fifth-wave HPAI H7N9 viruses have gained the ability to cause enhanced disease in mammalian models and with further adaptation may acquire the ability to cause an H7N9 pandemic. IMPORTANCE The potential pandemic risk posed by avian influenza H7N9 viruses was heightened during the fifth epidemic wave in China due to the sudden increase in the number of human infections and the emergence of antigenically distinct LPAI and HPAI H7N9 viruses. In this study, a group of fifth-wave HPAI and LPAI viruses was evaluated for its ability to infect, cause disease, and transmit in small-animal models. The ability of HPAI H7N9 viruses to cause more severe disease and to replicate in brain tissues in animal models as well as their ability to fuse at a lower pH threshold than LPAI H7N9 viruses suggests that the fifth-wave H7N9 viruses have evolved to acquire novel traits with the potential to pose a higher risk to humans. Although the fifth-wave H7N9 viruses have not yet gained the ability to transmit efficiently by air, continuous surveillance and risk assessment remain essential parts of our pandemic preparedness efforts., (Copyright © 2018 American Society for Microbiology.)
- Published
- 2018
- Full Text
- View/download PDF
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