What about good ole’ Ralphie???

SEE:
2018 https://pubmed.ncbi.nlm.nih.gov/?term=ralph%20Baric%20CoV&sort=date&page=19

2017 https://pubmed.ncbi.nlm.nih.gov/?term=ralph%20Baric%20CoV&sort=date&page=18

(pages are continuous so that is just rough)

This is what he was working on in the time frame when I came down with Covid in the fall of 2018 (NOT 2019.) These are just a few of the papers picked at random. Remember the publication date would be months or years after the actual lab work.

July 24 2019
Increasing the translation of mouse models of MERS coronavirus pathogenesis through kinetic hematological analysis

Leist SR, Jensen KL, Baric RS, Sheahan TP.PLoS One. 2019 Jul 24;14(7):e0220126.
(All the authors are located @ UNC Chapel Hill NC)
.

Abstract

Newly emerging viral pathogens pose a constant and unpredictable threat to human and animal health. Coronaviruses (CoVs) have a penchant for sudden emergence, as evidenced by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV) and most recently, swine acute diarrhea syndrome coronavirus (SADS-CoV). Small animal models of emerging viral pathogenesis are crucial to better understand the virus and host factors driving disease progression. However, rodent models are often criticized for their limited translatability to humans…

We recently generated a mouse model for MERS-CoV pathogenesis through the humanization of the orthologous entry receptor dipeptidyl peptidase 4 (DPP4). {There is those humanized mice]…. To increase the translatability of this model, we validated and established the use of an automated veterinary hematology analyzer (VetScan HM5) at biosafety level 3 for analysis of peripheral blood. MERS-CoV lung titer peaked 2 days post infection concurrent with lymphopenia and neutrophilia in peripheral blood, two phenomena also observed in MERS-CoV infection of humans….

 …

April 23 2017
Jumping species-a mechanism for coronavirus persistence and survival.
ALL University of North Carolina at Chapel Hill, Chapel Hill, NC,
Menachery VD, Graham RL, Baric RS.Curr Opin Virol. 2017 Apr;23:1-7. doi:

In this review, we explore the host and viral dynamics that shape these CoV populations for survival, amplification, and possible emergence in novel hosts….

June 7, 2017
Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice.
Gralinski LE, Menachery VD, Morgan AP, Totura AL, Beall A, Kocher J, Plante J, Harrison-Shostak DC, Schäfer A, Pardo-Manuel de Villena F, Ferris MT, Baric RS.G3 (Bethesda). 2017 Jun 7;7(6):1653-1663.
(all UNC)

Abstract

Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV)….These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses.

Remember there were some thoughts that Covid-19 was targeted at specific geno-types?

July 16 2018
A spike-modified Middle East respiratory syndrome coronavirus (MERS-CoV) infectious clone elicits mild respiratory disease in infected rhesus macaques.
Cockrell AS, Johnson JC, Moore IN, Liu DX, Bock KW, Douglas MG, Graham RL, Solomon J, Torzewski L, Bartos C, Hart R, Baric RS, Johnson RF.Sci Rep. 2018 Jul 16;8(1):10727.

Affiliations are very interesting, besides UNC you have from NIAIS-NIH (fauci)
Integrated Research Facility, Infectious Disease Pathogenesis Section, Emerging Viral Pathogens Section, Laboratory of Immunoregulation, Division of Intramural Research,  and lastly

Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702, USA.

Abstract

The recurrence of new human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) underscores the need for effective therapeutic countermeasures. Nonhuman primate models are considered the gold standard for preclinical evaluation of therapeutic countermeasures. However, MERS-CoV-induced severe respiratory disease in humans is associated with high viral loads in the lower respiratory tract, which may be difficult to achieve in nonhuman primate models. Considering this limitation, we wanted to ascertain the effectiveness of using a MERS-CoV infectious clone (icMERS-0) previously shown to replicate to higher titers than the wild-type EMC 2012 strain. We observed respiratory disease resulting from exposure to the icMERS-0 strain as measured by CT in rhesus monkeys with concomitant detection of virus antigen by immunohistochemistry. Overall, respiratory disease was mild and transient, resolving by day 30 post-infection. Although pulmonary disease was mild, these results demonstrate for the first time the utility of CT imaging to measure disease elicited by a MERS-CoV infectious clone system in nonhuman primate models.

August 16 2018
Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines.
Menachery VD, Gralinski LE, Mitchell HD, Dinnon KH 3rd, Leist SR, Yount BL Jr, McAnarney ET, Graham RL, Waters KM, Baric RS.J Virol. 2018 Aug 16;

Affiliations

• 1 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
• 3 Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
• 4 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Abstract

With an ongoing threat posed by circulating zoonotic strains, new strategies are required to prepare for the next emergent coronavirus (CoV). Previously, groups had targeted conserved coronavirus proteins as a strategy to generate live attenuated vaccine strains against current and future CoVs. With this in mind, we explored whether manipulation of CoV NSP16, a conserved 2’O methyltransferase (MTase), could provide a broad attenuation platform against future emergent strains. Using the severe acute respiratory syndrome-CoV mouse model, an NSP16 mutant vaccine was evaluated for protection from heterologous challenge, efficacy in the aging host, and potential for reversion to pathogenesis. Despite some success, concerns for virulence in the aged and potential for reversion makes targeting NSP16 alone an untenable approach. However, combining a 2’O MTase mutation with a previously described CoV fidelity mutant produced a vaccine strain capable of protection from heterologous virus challenge, efficacy in aged mice, and no evidence for reversion. Together, the results indicate that targeting the CoV 2’O MTase in parallel with other conserved attenuating mutations may provide a platform strategy for rapidly generating live attenuated coronavirus vaccines.IMPORTANCE Emergent coronaviruses remain a significant threat to global public health and rapid response vaccine platforms are needed to stem future outbreaks. However, failure of many previous CoV vaccine formulations has clearly highlighted the need to test efficacy under different conditions and especially in vulnerable populations such as the aged and immunocompromised. This study illustrates that despite success in young models, the 2’O methyltransferase mutant carries too much risk for pathogenesis and reversion in vulnerable models to be used as a stand-alone vaccine strategy. Importantly, the 2’O methyltransferase mutation can be paired with other attenuating approaches to provide robust protection from heterologous challenge and in vulnerable populations. Coupled with increased safety and reduced pathogenesis, the study highlights the potential for 2’O methyltransferase attenuation as a major component of future live attenuated coronavirus vaccines.

December 23 2017
Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease.
Douglas MG, Kocher JF, Scobey T, Baric RS, Cockrell AS.Virology. 2018 Apr;5
(All UNC)

Abstract

We recently established a mouse model (288-330+/+) that developed acute respiratory disease resembling human pathology following infection with a high dose (5 × 106 PFU) of mouse-adapted MERS-CoV (icMERSma1). Although this high dose conferred fatal respiratory disease in mice, achieving similar pathology at lower viral doses may more closely reflect naturally acquired infections. Through continued adaptive evolution of icMERSma1 we generated a novel mouse-adapted MERS-CoV (maM35c4) capable of achieving severe respiratory disease at doses between 103 and 105 PFU. Novel mutations were identified in the maM35c4 genome that may be responsible for eliciting etiologies of acute respiratory distress syndrome at 10-1000 fold lower viral doses. Importantly, comparative genetics of the two mouse-adapted MERS strains allowed us to identify specific mutations that remained fixed through an additional 20 cycles of adaptive evolution. Our data indicate that  the extent of MERS-CoV adaptation determines the minimal infectious dose required to achieve severe respiratory disease.

The fuckers were working to make SARS MORE CONTAGIOUS at lower number of virus ‘particles’ 

Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis.
Menachery VD, Gralinski LE, Mitchell HD, Dinnon KH 3rd, Leist SR, Yount BL Jr, Graham RL, McAnarney ET, Stratton KG, Cockrell AS, Debbink K, Sims AC, Waters KM, Baric RS.mSphere. 2017 Nov 15

Affiliations

• 1 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
• 2 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
• 3 Pacific Northwest National Laboratory, Richland, Washington, USA.
• 4 Department of Natural Sciences, Bowie State University, Bowie, Maryland, USA.
• 5 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Abstract

Coronaviruses (CoVs) encode a mixture of highly conserved and novel genes, as well as genetic elements necessary for infection and pathogenesis, raising the possibility of common targets for attenuation and therapeutic design….

Importantly, the robust attenuation permitted the use of dNSP16 mutant MERS-CoV as a live attenuated vaccine platform protecting from a challenge with a mouse-adapted MERS-CoV strain. …IMPORTANCE Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2′O-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2′O-MTase function across CoVs.

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So Ralphie was certainly playing with his pet Covid Viruses during the time frame I got the Baric Virus in 2018.