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1.
Pharmacol Res Perspect ; 10(1): e00922, 2022 02.
Article in English | MEDLINE | ID: covidwho-1664440

ABSTRACT

Why a systems analysis view of this pandemic? The current pandemic has inflicted almost unimaginable grief, sorrow, loss, and terror at a global scale. One of the great ironies with the COVID-19 pandemic, particularly early on, is counter intuitive. The speed at which specialized basic and clinical sciences described the details of the damage to humans in COVID-19 disease has been impressive. Equally, the development of vaccines in an amazingly short time interval has been extraordinary. However, what has been less well understood has been the fundamental elements that underpin the progression of COVID-19 in an individual and in populations. We have used systems analysis approaches with human physiology and pharmacology to explore the fundamental underpinnings of COVID-19 disease. Pharmacology powerfully captures the thermodynamic characteristics of molecular binding with an exogenous entity such as a virus and its consequences on the living processes well described by human physiology. Thus, we have documented the passage of SARS-CoV-2 from infection of a single cell to species jump, to tropism, variant emergence and widespread population infection. During the course of this review, the recurrent observation was the efficiency and simplicity of one critical function of this virus. The lethality of SARS-CoV-2 is due primarily to its ability to possess and use a variable surface for binding to a specific human target with high affinity. This binding liberates Gibbs free energy (GFE) such that it satisfies the criteria for thermodynamic spontaneity. Its binding is the prelude to human host cellular entry and replication by the appropriation of host cell constituent molecules that have been produced with a prior energy investment by the host cell. It is also a binding that permits viral tropism to lead to high levels of distribution across populations with newly formed virions. This thermodynamic spontaneity is repeated endlessly as infection of a single host cell spreads to bystander cells, to tissues, to humans in close proximity and then to global populations. The principal antagonism of this process comes from SARS-CoV-2 itself, with its relentless changing of its viral surface configuration, associated with the inevitable emergence of variants better configured to resist immune sequestration and importantly with a greater affinity for the host target and higher infectivity. The great value of this physiological and pharmacological perspective is that it reveals the fundamental thermodynamic underpinnings of SARS-CoV-2 infection.


Subject(s)
COVID-19/etiology , SARS-CoV-2/physiology , Systems Analysis , Thermodynamics , Animals , COVID-19/drug therapy , Chiroptera/virology , Humans , Inflammasomes/physiology , Nasopharynx/virology , Viral Tropism , Virus Internalization
3.
Pharmacol Res Perspect ; 10(1): e00917, 2022 02.
Article in English | MEDLINE | ID: covidwho-1664438

ABSTRACT

SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1 R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.


Subject(s)
COVID-19/etiology , Renin-Angiotensin System/physiology , SARS-CoV-2/physiology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/physiology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Humans , Inflammation/etiology , Renin/antagonists & inhibitors
4.
Pharmacol Res Perspect ; 10(1): e00911, 2022 02.
Article in English | MEDLINE | ID: covidwho-1625316

ABSTRACT

Infection of humans with SARS-CoV-2 virus causes a disease known colloquially as "COVID-19" with symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due to the virus binding to the ACE-2 protein on endothelial cells lining blood vessels and entering these cells in order to replicate. Viral replication causes oxidative stress due to elevated levels of reactive oxygen species. Many (~60%) of the infected people appear to have eliminated the virus from their body after 28 days and resume normal activity. However, a significant proportion (~40%) experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, "brain fog," insomnia, shortness of breath, and tachycardia) after 12 weeks and are diagnosed with a syndrome named "LONG COVID." Longitudinal clinical studies in a group of subjects who were infected with SARS-CoV-2 have been compared to a non-infected matched group of subjects. A cohort of infected subjects can be identified by a battery of cytokine markers to have persistent, low level grade of inflammation and often self-report two or more troubling symptoms. There is no drug that will relieve their symptoms effectively. It is hypothesized that drugs that activate the intracellular transcription factor, nuclear factor erythroid-derived 2-like 2 (NRF2) may increase the expression of enzymes to synthesize the intracellular antioxidant, glutathione that will quench free radicals causing oxidative stress. The hormone melatonin has been identified as an activator of NRF2 and a relatively safe chemical for most people to ingest chronically. Thus, it is an option for consideration of re-purposing studies in "LONG COVID" subjects experiencing insomnia, depression, fatigue, and "brain fog" but not tachycardia. Appropriately designed clinical trials are required to evaluate melatonin.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/complications , Biomarkers/metabolism , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/virology , Endothelium, Vascular/virology , Humans , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Virus Replication
5.
Non-conventional in English | [Unspecified Source], Grey literature | ID: grc-750512

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.

6.
8.
J Neurodev Disord ; 13(1): 31, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1381252

ABSTRACT

BACKGROUND: Transmission of SARS-CoV-2 in schools primarily for typically developing children is rare. However, less is known about transmission in schools for children with intellectual and developmental disabilities (IDD), who are often unable to mask or maintain social distancing. The objectives of this study were to determine SARS-CoV-2 positivity and in-school transmission rates using weekly screening tests for school staff and students and describe the concurrent deployment of mitigation strategies in six schools for children with IDD. METHODS: From November 23, 2020, to May, 28, 2021, weekly voluntary screening for SARS-CoV-2 with a high sensitivity molecular-based saliva test was offered to school staff and students. Weekly positivity rates were determined and compared to local healthcare system and undergraduate student screening data. School-based transmission was assessed among participants quarantined for in-school exposure. School administrators completed a standardized survey to assess school mitigation strategies. RESULTS: A total of 59 students and 416 staff participated. An average of 304 school staff and students were tested per week. Of 7289 tests performed, 21 (0.29%) new SARS-CoV-2 positive cases were identified. The highest weekly positivity rate was 1.2% (n = 4) across all schools, which was less than community positivity rates. Two cases of in-school transmission were identified, each among staff, representing 2% (2/103) of participants quarantined for in-school exposure. Mitigation strategies included higher than expected student mask compliance, reduced room capacity, and phased reopening. CONCLUSIONS: During 24 weeks that included the peak of the COVID-19 pandemic in winter 2020-21, we found lower rates of SARS-CoV-2 screening test positivity among staff and students of six schools for children with IDD compared to community rates. In-school transmission of SARS-CoV-2 was low among those quarantined for in-school exposure. However, the impact of the emerging SARS-CoV-2 Delta variant on the effectiveness of these proven mitigation strategies remains unknown. TRIAL REGISTRATION: Prior to enrollment, this study was registered at ClinicalTrials.gov on September 25, 2020, identifier NCT04565509 , titled Supporting the Health and Well-being of Children with Intellectual and Developmental Disability During COVID-19 Pandemic.


Subject(s)
COVID-19 , SARS-CoV-2 , Child , Developmental Disabilities/diagnosis , Developmental Disabilities/epidemiology , Humans , Pandemics , Schools
9.
Br J Nutr ; : 1-6, 2021 Jun 03.
Article in English | MEDLINE | ID: covidwho-1253843
10.
Cell ; 184(7): 1804-1820.e16, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1084553

ABSTRACT

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.


Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , CD8-Positive T-Lymphocytes , COVID-19 , Immunoglobulin Fc Fragments/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CHO Cells , COVID-19/immunology , COVID-19/therapy , Chlorocebus aethiops , Cricetulus , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , SARS-CoV-2/immunology , Vero Cells , Viral Load
11.
Br J Clin Pharmacol ; 87(3): 875-885, 2021 03.
Article in English | MEDLINE | ID: covidwho-933967

ABSTRACT

With any new disease a framework for the development of preventative or treatment therapeutics is key; the absence of such in COVID-19 has enabled ineffective and potentially unsafe treatments to be taken up by governments and clinicians desperate to have options for patients. As we still have few therapies and nil vaccines yet available, the void of a clear framework for research and practice is increasingly clear. We describe a framework that has been used to prioritise therapeutic research in previous pandemics which could be used to progress clinical pharmacology and therapeutics research in COVID-19. This is particularly relevant as discussion has already moved on from antiviral therapeutics to delineating the treatment of the host from treatment and elimination of the infective agent. Focussing on the host brings together three concepts: host treatment, the damage response framework and therapeutic repurposing. The integration of these three areas plays to the traditional strength of pharmaceuticals in providing a period of stabilization to permit time for the development of novel antiviral drugs and vaccines. In integrating approaches to repurposing, host treatment and damage response we identified three key properties that a potentially effective repurposed drug must possess by way of a framework. There must be homology, i.e., the same or similar relation with the pathogenesis of the disease, ideally targeted to the conserved pathophysiological outcomes of the viral attack; there must be a defined locus within the spectrum to prevention to severe disease and the framework must draw upon the historical dose and safety experience of the repurposed drug. To illustrate, we have mapped therapeutics that impact upon a key dysregulated pathway in COVID-19 - the renin angiotensin system - using this approach. Collectively this type of analysis reveals the importance of existing data (repurposed information and administrative observational data) and the importance of the details of the known pathophysiological response to viruses in approaches to treating the host.


Subject(s)
COVID-19/drug therapy , Drug Repositioning , Antiviral Agents/therapeutic use , COVID-19/immunology , Humans , Immunity, Innate/drug effects , Pandemics
12.
Clin Chem ; 67(2): 415-424, 2021 01 30.
Article in English | MEDLINE | ID: covidwho-887266

ABSTRACT

BACKGROUND: Rapid, reliable, and widespread testing is required to curtail the ongoing COVID-19 pandemic. Current gold-standard nucleic acid tests are hampered by supply shortages in critical reagents including nasal swabs, RNA extraction kits, personal protective equipment, instrumentation, and labor. METHODS: To overcome these challenges, we developed a rapid colorimetric assay using reverse-transcription loop-mediated isothermal amplification (RT-LAMP) optimized on human saliva samples without an RNA purification step. We describe the optimization of saliva pretreatment protocols to enable analytically sensitive viral detection by RT-LAMP. We optimized the RT-LAMP reaction conditions and implemented high-throughput unbiased methods for assay interpretation. We tested whether saliva pretreatment could also enable viral detection by conventional reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Finally, we validated these assays on clinical samples. RESULTS: The optimized saliva pretreatment protocol enabled analytically sensitive extraction-free detection of SARS-CoV-2 from saliva by colorimetric RT-LAMP or RT-qPCR. In simulated samples, the optimized RT-LAMP assay had a limit of detection of 59 (95% confidence interval: 44-104) particle copies per reaction. We highlighted the flexibility of LAMP assay implementation using 3 readouts: naked-eye colorimetry, spectrophotometry, and real-time fluorescence. In a set of 30 clinical saliva samples, colorimetric RT-LAMP and RT-qPCR assays performed directly on pretreated saliva samples without RNA extraction had accuracies greater than 90%. CONCLUSIONS: Rapid and extraction-free detection of SARS-CoV-2 from saliva by colorimetric RT-LAMP is a simple, sensitive, and cost-effective approach with broad potential to expand diagnostic testing for the virus causing COVID-19.


Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19/diagnosis , Nucleic Acid Amplification Techniques/methods , RNA, Viral/analysis , SARS-CoV-2/isolation & purification , Saliva/virology , COVID-19/epidemiology , Colorimetry/methods , Endopeptidase K/chemistry , Humans , Limit of Detection , Pandemics , Point-of-Care Testing , SARS-CoV-2/chemistry
13.
Nat Immunol ; 21(11): 1327-1335, 2020 11.
Article in English | MEDLINE | ID: covidwho-728991

ABSTRACT

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Immunity, Innate/immunology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Pneumonia/pathology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/immunology , Disease Models, Animal , Female , Humans , Interferon Type I/immunology , Interferon-gamma/immunology , Keratin-18/genetics , Leukocytes/immunology , Lymphocyte Activation/immunology , Male , Mice , Mice, Transgenic , Monocytes/immunology , NF-kappa B/immunology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Pandemics , Pneumonia/genetics , Pneumonia/virology , Pneumonia, Viral/immunology , Promoter Regions, Genetic/genetics , SARS-CoV-2 , T-Lymphocytes/immunology , Vero Cells , Virus Replication/immunology
14.
bioRxiv ; 2020 Jul 10.
Article in English | MEDLINE | ID: covidwho-665969

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.

15.
Pharmacol Res Perspect ; 8(4): e00620, 2020 08.
Article in English | MEDLINE | ID: covidwho-611146

ABSTRACT

In 2016 Fedson stated …. "For almost two decades, leading scientists and health officials have warned that we must prepare for a potentially devastating global pandemic of an infectious disease. Initial concern was focused on …H5N1…. More recently…a devastating outbreak of Ebola virus..(and) several other emerging viruses are believed to seriously threaten global health and global security. To prepare, scientists have been urged to discover new vaccines and treatments for these emerging viruses. At the same time, political leaders have been urged by global health experts to invest millions in a "top down" restructuring of the global health system. This article takes a different view. It focuses on an alternative approach to the scientific discovery of treatments for individual patients, reviews the mechanisms of action and clinical experience with specific drugs that might be useful, and considers whether or not recent lessons regarding this "bottom up" approach to treatment have been learned". Now with a new virus and pandemic upon us, Fedson's 2016 comments appear chilling, are cause for reflection on what we have learnt and importantly offer focus on an immediate opportunity in the area of treating the host (Fedson DS, Ann Transl Med, 2016;4:421).


Subject(s)
COVID-19/drug therapy , Drug Repositioning/methods , Global Health , COVID-19/epidemiology , Delivery of Health Care/organization & administration , Disease Outbreaks/prevention & control , Humans , Pandemics/prevention & control
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