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Article ; Online: The Importance of "Negative" Results: Lipid Lessons in Coronavirus Biology.

Leist, Sarah R / Mock, Jason R

American journal of respiratory cell and molecular biology

2023 Volume 69, Issue 6, Page(s) 610–611

MeSH term(s)	Mice ; Animals ; SARS-CoV-2 ; COVID-19 ; Hydroxycholesterols ; Biology
Chemical Substances	25-hydroxycholesterol (767JTD2N31) ; Hydroxycholesterols
Language	English
Publishing date	2023-10-26
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2023-0301ED
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Article ; Online: Genetically Engineering a Susceptible Mouse Model for MERS-CoV-Induced Acute Respiratory Distress Syndrome.

Leist, Sarah R / Cockrell, Adam S

Methods in molecular biology (Clifton, N.J.)

2020 Volume 2099, Page(s) 137–159

Abstract: Since 2012, monthly cases of Middle East respiratory syndrome coronavirus (MERS-CoV) continue to cause severe respiratory disease that is fatal in ~35% of diagnosed individuals. The ongoing threat to global public health and the need for novel ... ...

Abstract	Since 2012, monthly cases of Middle East respiratory syndrome coronavirus (MERS-CoV) continue to cause severe respiratory disease that is fatal in ~35% of diagnosed individuals. The ongoing threat to global public health and the need for novel therapeutic countermeasures have driven the development of animal models that can reproducibly replicate the pathology associated with MERS-CoV in human infections. The inability of MERS-CoV to replicate in the respiratory tracts of mice, hamsters, and ferrets stymied initial attempts to generate small animal models. Identification of human dipeptidyl peptidase IV (hDPP4) as the receptor for MERS-CoV infection opened the door for genetic engineering of mice. Precise molecular engineering of mouse DPP4 (mDPP4) with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology maintained inherent expression profiles, and limited MERS-CoV susceptibility to tissues that naturally express mDPP4, notably the lower respiratory tract wherein MERS-CoV elicits severe pulmonary pathology. Here, we describe the generation of the 288-330
MeSH term(s)	Animals ; CRISPR-Cas Systems ; Coronavirus Infections/pathology ; Coronavirus Infections/virology ; Dipeptidyl Peptidase 4/genetics ; Dipeptidyl Peptidase 4/metabolism ; Disease Models, Animal ; Disease Susceptibility ; Female ; Genetic Engineering ; Humans ; Lung/virology ; Male ; Mice/genetics ; Mice, Inbred C57BL ; Middle East Respiratory Syndrome Coronavirus/physiology ; Respiratory Distress Syndrome, Adult/pathology ; Respiratory Distress Syndrome, Adult/virology
Chemical Substances	DPP4 protein, human (EC 3.4.14.5) ; Dipeptidyl Peptidase 4 (EC 3.4.14.5) ; Dpp4 protein, mouse (EC 3.4.14.5)
Keywords	covid19
Language	English
Publishing date	2020-01-09
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0211-9_12
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Article ; Online: Attitudes, beliefs, knowledge, and practices for over-the-counter syringe sales in community pharmacies: A systematic review.

Gionfriddo, Michael R / Owens, Katelyn M / Leist, Sarah E / Schrum, Luke T / Covvey, Jordan R

Journal of the American Pharmacists Association : JAPhA

2023 Volume 63, Issue 5, Page(s) 1472–1489.e3

Abstract: Background: Community pharmacies are an important resource for people who inject drugs (PWID) to purchase over-the-counter (OTC) syringes. Access to sterile injection equipment can reduce the transmission of blood-borne illnesses. However, pharmacists ... ...

Abstract	Background: Community pharmacies are an important resource for people who inject drugs (PWID) to purchase over-the-counter (OTC) syringes. Access to sterile injection equipment can reduce the transmission of blood-borne illnesses. However, pharmacists and their staff ultimately use discretion over sales. Objective: To identify staff attitudes, beliefs, knowledge, and practices in the sale of OTC syringes in community pharmacies. Methods: This systematic review was reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and registered with PROSPERO (CRD42022363040). We systematically searched PubMed, Embase, and Scopus from inception to September 2022. The review included peer-reviewed empirical studies regarding OTC syringe sales among community pharmacy staff (pharmacists, interns, and technicians). We screened records and extracted data using a predefined data extraction form. Findings were narratively synthesized, and critical appraisal was conducted using the Mixed Methods Appraisal Tool. Results: A total of 1895 potentially relevant articles were identified, and 35 were included. Most studies (23; 63.9%) were cross-sectional descriptive designs. All studies included pharmacists, with seven (19.4%) also including technicians, two (5.6%) including interns, and four (11.1%) including other staff. Studies found relatively high support among respondents for harm reduction-related services within community pharmacies, but less common reports of staff engaging in said services themselves. When studies investigated the perceived positive or negative impacts of OTC syringe sales, prevention of blood-borne illness was widely understood as a benefit, while improper syringe disposal and safety of the pharmacy and its staff commonly reported as concerns. Stigmatizing attitudes/beliefs toward PWID were prevalent across studies. Conclusion: Community pharmacy staff report knowledge regarding the benefits of OTC syringes, but personal attitudes/beliefs heavily influence decisions to engage in sales. Despite support for various syringe-related harm reduction activities, offerings of services were less likely due to concerns around PWID.
MeSH term(s)	Humans ; Syringes ; Pharmacies ; Substance Abuse, Intravenous ; Attitude of Health Personnel ; Pharmaceutical Services ; Nonprescription Drugs ; Pharmacists ; HIV Infections/prevention & control
Chemical Substances	Nonprescription Drugs
Language	English
Publishing date	2023-07-08
Publishing country	United States
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	2118585-2
ISSN	1544-3450 ; 1544-3191 ; 1086-5802
ISSN (online)	1544-3450
ISSN	1544-3191 ; 1086-5802
DOI	10.1016/j.japh.2023.07.001
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Article ; Online: Cell and animal models of SARS-CoV-2 pathogenesis and immunity.

Leist, Sarah R / Schäfer, Alexandra / Martinez, David R

Disease models & mechanisms

2020 Volume 13, Issue 9

Abstract: The spread of the novel virus SARS coronavirus 2 (SARS-CoV-2) was explosive, with cases first identified in December 2019, and >22 million people infected and >775,000 deaths as of August 2020. SARS-CoV-2 can cause severe respiratory disease in humans ... ...

Abstract	The spread of the novel virus SARS coronavirus 2 (SARS-CoV-2) was explosive, with cases first identified in December 2019, and >22 million people infected and >775,000 deaths as of August 2020. SARS-CoV-2 can cause severe respiratory disease in humans leading to coronavirus disease 2019 (COVID-19). The development of effective clinical interventions, such as antivirals and vaccines that can limit or even prevent the burden and spread of SARS-CoV-2, is a global health priority. Testing of leading antivirals, monoclonal antibody therapies and vaccines against SARS-CoV-2 will require robust animal and cell models of viral pathogenesis. In this Special Article, we discuss the cell-based and animal models of SARS-CoV-2 infection and pathogenesis that have been described as of August 2020. We also outline the outstanding questions for which researchers can leverage animal and cell-based models to improve our understanding of SARS-CoV-2 pathogenesis and protective immunity. Taken together, the refinement of models of SARS-CoV-2 infection will be critical to guide the development of therapeutics and vaccines against SARS-CoV-2 to end the COVID-19 pandemic.
MeSH term(s)	Animals ; Antiviral Agents/therapeutic use ; Betacoronavirus/drug effects ; Betacoronavirus/immunology ; Betacoronavirus/pathogenicity ; COVID-19 ; COVID-19 Vaccines ; Cells, Cultured ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Coronavirus Infections/prevention & control ; Coronavirus Infections/virology ; Disease Models, Animal ; Host Microbial Interactions ; Humans ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Pneumonia, Viral/virology ; SARS-CoV-2 ; Species Specificity ; Tissue Culture Techniques ; Viral Vaccines/therapeutic use ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; COVID-19 Vaccines ; Viral Vaccines
Keywords	covid19
Language	English
Publishing date	2020-09-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.046581
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Article: Giving the Genes a Shuffle: Using Natural Variation to Understand Host Genetic Contributions to Viral Infections.

Leist, Sarah R / Baric, Ralph S

Trends in genetics : TIG

2018 Volume 34, Issue 10, Page(s) 777–789

Abstract: The laboratory mouse has proved an invaluable model to identify host factors that regulate the progression and outcome of virus-induced disease. The paradigm is to use single-gene knockouts in inbred mouse strains or genetic mapping studies using ... ...

Abstract	The laboratory mouse has proved an invaluable model to identify host factors that regulate the progression and outcome of virus-induced disease. The paradigm is to use single-gene knockouts in inbred mouse strains or genetic mapping studies using biparental mouse populations. However, genetic variation among these mouse strains is limited compared with the diversity seen in human populations. To address this disconnect, a multiparental mouse population has been developed to specifically dissect the multigenetic regulation of complex disease traits. The Collaborative Cross (CC) population of recombinant inbred mouse strains is a well-suited systems-genetics tool to identify susceptibility alleles that control viral and microbial infection outcomes and immune responses and to test the promise of personalized medicine.
MeSH term(s)	Animals ; Chromosome Mapping ; Disease Models, Animal ; Genetic Predisposition to Disease ; Genetics, Population ; Humans ; Mice ; Mice, Inbred Strains/genetics ; Mice, Inbred Strains/virology ; Mice, Knockout ; Quantitative Trait Loci/genetics ; Virus Diseases/genetics ; Virus Diseases/virology
Keywords	covid19
Language	English
Publishing date	2018-08-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2018.07.005
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Article: Mouse Adapted SARS-CoV-2 Model Induces "Long-COVID" Neuropathology in BALB/c Mice.

Gressett, Timothy E / Leist, Sarah R / Ismael, Saifudeen / Talkington, Grant / Dinnon, Kenneth H / Baric, Ralph S / Bix, Gregory

bioRxiv : the preprint server for biology

2023

Abstract: The novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality and continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms to include neuro-psychological dysfunction, ...

Abstract	The novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality and continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms to include neuro-psychological dysfunction, termed "Long COVID", which can cause significant reduction of quality of life. Despite vigorous model development, the possible cause of these symptoms and the underlying pathophysiology of this devastating disease remains elusive. Mouse adapted (MA10) SARS-CoV-2 is a novel mouse-based model of COVID-19 which simulates the clinical symptoms of respiratory distress associated with SARS-CoV-2 infection in mice. In this study, we evaluated the long-term effects of MA10 infection on brain pathology and neuroinflammation. 10-week and 1-year old female BALB/cAnNHsd mice were infected intranasally with 10
Language	English
Publishing date	2023-03-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.18.533204
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Article ; Online: Divergent pathogenetic outcomes in BALB/c mice following Omicron subvariant infection.

Powers, John M / Leist, Sarah R / Mallory, Michael L / Yount, Boyd L / Gully, Kendra L / Zweigart, Mark R / Bailey, Alexis B / Sheahan, Timothy P / Harkema, Jack R / Baric, Ralph S

Virus research

2024 Volume 341, Page(s) 199319

Abstract: Following the emergence of B.1.1.529 Omicron, the SARS-CoV-2 virus evolved into a significant number of sublineage variants that possessed numerous mutations throughout the genome, but particularly within the spike glycoprotein (S) gene. For example, the ...

Abstract	Following the emergence of B.1.1.529 Omicron, the SARS-CoV-2 virus evolved into a significant number of sublineage variants that possessed numerous mutations throughout the genome, but particularly within the spike glycoprotein (S) gene. For example, the BQ.1.1 and the XBB.1 and XBB.1.5 subvariants contained 34 and 41 mutations in S, respectively. However, these variants elicited largely replication only or mild disease phenotypes in mice. To better model pathogenic outcomes and measure countermeasure performance, we developed mouse adapted versions (BQ.1.1 MA; XBB.1 MA; XBB.1.5 MA) that reflect more pathogenic acute phase pulmonary disease symptoms of SARS-CoV-2, as well as derivative strains expressing nano-luciferase (nLuc) in place of ORF7 (BQ.1.1 nLuc; XBB.1 nLuc; XBB.1.5 nLuc). Amongst the mouse adapted (MA) viruses, a wide range of disease outcomes were observed including mortality, weight loss, lung dysfunction, and tissue viral loads in the lung and nasal turbinates. Intriguingly, XBB.1 MA and XBB.1.5 MA strains, which contained identical mutations throughout except at position F486S/P in S, exhibited divergent disease outcomes in mice (Ao et al., 2023). XBB.1.5 MA infection was associated with significant weight loss and ∼45 % mortality across two independent studies, while XBB.1 MA infected animals suffered from mild weight loss and only 10 % mortality across the same two independent studies. Additionally, the development and use of nanoluciferase expressing strains provided moderate throughput for live virus neutralization assays. The availability of small animal models for the assessment of Omicron VOC disease potential will enable refined capacity to evaluate the efficacy of on market and pre-clinical therapeutics and interventions.
MeSH term(s)	Animals ; Mice ; Mice, Inbred BALB C ; Mutation ; Phenotype ; SARS-CoV-2 ; Weight Loss
Language	English
Publishing date	2024-01-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2024.199319
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Article: Genetically Engineering a Susceptible Mouse Model for MERS-CoV-Induced Acute Respiratory Distress Syndrome

Leist, Sarah R / Cockrell, Adam S

Methods Mol Biol

Abstract	Since 2012, monthly cases of Middle East respiratory syndrome coronavirus (MERS-CoV) continue to cause severe respiratory disease that is fatal in ~35% of diagnosed individuals. The ongoing threat to global public health and the need for novel therapeutic countermeasures have driven the development of animal models that can reproducibly replicate the pathology associated with MERS-CoV in human infections. The inability of MERS-CoV to replicate in the respiratory tracts of mice, hamsters, and ferrets stymied initial attempts to generate small animal models. Identification of human dipeptidyl peptidase IV (hDPP4) as the receptor for MERS-CoV infection opened the door for genetic engineering of mice. Precise molecular engineering of mouse DPP4 (mDPP4) with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology maintained inherent expression profiles, and limited MERS-CoV susceptibility to tissues that naturally express mDPP4, notably the lower respiratory tract wherein MERS-CoV elicits severe pulmonary pathology. Here, we describe the generation of the 288-330+/+ MERS-CoV mouse model in which mice were made susceptible to MERS-CoV by modifying two amino acids on mDPP4 (A288 and T330), and the use of adaptive evolution to generate novel MERS-CoV isolates that cause fatal respiratory disease. The 288-330+/+ mice are currently being used to evaluate novel drug, antibody, and vaccine therapeutic countermeasures for MERS-CoV. The chapter starts with a historical perspective on the emergence of MERS-CoV and animal models evaluated for MERS-CoV pathogenesis, and then outlines the development of the 288-330+/+ mouse model, assays for assessing a MERS-CoV pulmonary infection in a mouse model, and describes some of the challenges associated with using genetically engineered mice.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #710924
Database	COVID19

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Article ; Online: Unique immune profiles in collaborative cross mice linked to survival and viral clearance upon infection.

Graham, Jessica B / Swarts, Jessica L / Leist, Sarah R / Schäfer, Alexandra / Bell, Timothy A / Hock, Pablo / Farrington, Joe / Shaw, Ginger D / Ferris, Martin T / Pardo-Manuel de Villena, Fernando / Baric, Ralph S / Lund, Jennifer M

iScience

2024 Volume 27, Issue 3, Page(s) 109103

Abstract: The response to infection is generally heterogeneous and diverse, with some individuals remaining asymptomatic while others present with severe disease or a diverse range of symptoms. Here, we address the role of host genetics on immune phenotypes and ... ...

Abstract	The response to infection is generally heterogeneous and diverse, with some individuals remaining asymptomatic while others present with severe disease or a diverse range of symptoms. Here, we address the role of host genetics on immune phenotypes and clinical outcomes following viral infection by studying genetically diverse mice from the Collaborative Cross (CC), allowing for use of a small animal model with controlled genetic diversity while maintaining genetic replicates. We demonstrate variation by deeply profiling a broad range of innate and adaptive immune cell phenotypes at steady-state in 63 genetically distinct CC mouse strains and link baseline immune signatures with virologic and clinical disease outcomes following infection of mice with herpes simplex virus 2 (HSV-2) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This work serves as a resource for CC strain selection based on steady-state immune phenotypes or disease presentation upon viral infection, and further, points to possible pre-infection immune correlates of survival and early viral clearance upon infection.
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109103
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Article: Efficacy of Host Cell Serine Protease Inhibitor MM3122 against SARS-CoV-2 for Treatment and Prevention of COVID-19.

Boon, Adrianus C M / L Bricker, Traci / Fritch, Ethan J / Leist, Sarah R / Gully, Kendra / Baric, Ralph S / Graham, Rachel L / Troan, Brigid V / Mahoney, Matthew / Janetka, James W

bioRxiv : the preprint server for biology

2024

Abstract: We have developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases including transmembrane protease serine 2 (TMPRSS2), matriptase and hepsin. TMPRSS2 is a membrane associated protease which is highly ... ...

Abstract	We have developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases including transmembrane protease serine 2 (TMPRSS2), matriptase and hepsin. TMPRSS2 is a membrane associated protease which is highly expressed in the upper and lower respiratory tract and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell receptor binding, entry, replication, and dissemination of new virion particles. We have previously shown that compound MM3122 exhibited sub nanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell-viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is also effective against the EG.5.1 variant of SARS-CoV-2. Further, we have evaluated MM3122 in a mouse model of COVID-19 and have demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion, and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in pro-inflammatory cytokines and chemokines production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2 infected mice. Therefore, MM3122 is a promising lead candidate small molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses. Importance: SARS-CoV-2 and other emerging RNA coronaviruses are a present and future threat in causing widespread endemic and pandemic infection and disease. In this paper, we have shown that the novel host-cell protease inhibitor, MM3122, blocks SARS-CoV-2 viral replication and is efficacious as both a prophylactic and therapeutic drug for the treatment of COVID-19 in mice. Targeting host proteins and pathways in antiviral therapy is an underexplored area of research but this approach promises to avoid drug resistance by the virus, which is common in current antiviral treatments.
Language	English
Publishing date	2024-02-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.09.579701
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