Dr. Jason Botten

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.

20 July 2021 in Science

Journal Article

Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2

+32

Targeting the main protease of SARS-CoV-2: Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al . identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice. —VV

2 October 2020 in PLOS Biology

Journal Article

Direct RT-qPCR detection of SARS-CoV-2 RNA from patient nasopharyngeal swabs without an RNA extraction step

Meei-Li Huang

Pheobe Laaguiby

+13

The ongoing COVID-19 pandemic has created an unprecedented need for rapid diagnostic testing. The World Health Organization (WHO) recommends a standard assay that includes an RNA extraction step from a nasopharyngeal (NP) swab followed by reverse transcription–quantitative polymerase chain reaction (RT-qPCR) to detect the purified SARS-CoV-2 RNA. The current global shortage of RNA extraction kits has caused a severe bottleneck to COVID-19 testing. The goal of this study was to determine whether SARS-CoV-2 RNA could be detected from NP samples via a direct RT-qPCR assay that omits the RNA extraction step altogether. The direct RT-qPCR approach correctly identified 92% of a reference set of blinded NP samples (n = 155) demonstrated to be positive for SARS-CoV-2 RNA by traditional clinical diagnostic RT-qPCR that included an RNA extraction. Importantly, the direct method had sufficient sensitivity to reliably detect those patients with viral loads that correlate with the presence of infectious virus. Thus, this strategy has the potential to ease supply choke points to substantially expand COVID-19 testing and screening capacity and should be applicable throughout the world.

21 March 2020 in bioRxiv

Preprint

DIRECT RT-qPCR DETECTION OF SARS-CoV-2 RNA FROM PATIENT NASOPHARYNGEAL SWABS WITHOUT AN RNA EXTRACTION STEP

Pheobe Laaguiby

+13

The ongoing COVID-19 pandemic has caused an unprecedented need for rapid diagnostic testing. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend a standard assay that includes an RNA extraction step from a nasopharyngeal (NP) swab followed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to detect the purified SARS-CoV-2 RNA. The current global shortage of RNA extraction kits has caused a severe bottleneck to COVID-19 testing. We hypothesized that SARS-CoV-2 RNA could be detected from NP samples via a direct RT-qPCR assay that omits the RNA extraction step altogether, and tested this hypothesis on a series of blinded clinical samples. The direct RT-qPCR approach correctly identified 92% of NP samples (n = 155) demonstrated to be positive for SARS-CoV-2 RNA by traditional clinical diagnostic RT-qPCR that included an RNA extraction. Thus, direct RT-qPCR could be a front-line approach to identify the substantial majority of COVID-19 patients, reserving a repeat test with RNA extraction for those individuals with high suspicion of infection but an initial negative result. This strategy would drastically ease supply chokepoints of COVID-19 testing and should be applicable throughout the world.

1 November 2013 in Cell Host & Microbe

Journal Article

The Intracellular Cargo Receptor ERGIC-53 Is Required for the Production of Infectious Arenavirus, Coronavirus, and Filovirus Particles

Joseph P. Klaus

Philip Eisenhauer

Joanne Russo

Anne B. Mason

Danh Do

Jason Botten

+10

1 July 2020 in Trends in Microbiology

Journal Article

Defective Interfering Particles of Negative-Strand RNA Viruses

Christopher M. Ziegler

Jason Botten

About Me

Dr. Jason Botten is a Professor of Medicine at the Immunobiology Unit, Department of Medicine, University of Vermont (since 2021). He earned his Ph.D. from the University of In New Mexico in 2000, he started his Post-doctoral research there. In 2002–2005, he worked as a postdoctoral fellow at The Scripps Research Institute (TSRI), and later as an Assistant Professor. In 2008, he moved to the University of Vermont and worked as an Assistant Professor. he is a member of the American Society of Microbiology, American Society of Tropical Medicine and Hygiene, American Society of Virology. His research focuses on host-pathogen interactions among pathogenic RNA viruses (e.g., arenaviruses, hantaviruses, and flaviviruses) and their incidental human hosts and natural animal or insect reservoirs. The major goals of his research program are to (i) discover key virus-host interactions that are essential for the virus and/or can be targeted for the development of therapeutics and vaccines, (ii) define the natural history of the human T and B cell responses to these pathogens and determine their contribution to protective immunity and/or immunopathologic disease, (iii) develop new cutting-edge assays and reagents for the field, and (iv) translate our most promising discoveries in therapeutics and vaccines.

Dr. Jason Botten

Dr. Jason Botten

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About Me