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1.
Mbio ; 12(2):9, 2021.
Article in English | Web of Science | ID: covidwho-1434904

ABSTRACT

The angiotensin-converting enzyme 2 (ACE2) receptor is a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host range determinant, and understanding SARS-CoV-2-ACE2 interactions will provide important insights into COVID-19 pathogenesis and animal model development. SARS-CoV-2 cannot infect mice due to incompatibility between its receptor binding domain and the murine ACE2 receptor. Through molecular modeling and empirical in vitro validation, we identified 5 key amino acid differences between murine and human ACE2 that mediate SARS-CoV-2 infection, generating a chimeric humanized murine ACE2. Additionally, we examined the ability of the humanized murine ACE2 receptor to permit infection by an additional preemergent group 2B coronavirus, WIV-1, providing evidence for the potential pan-virus capabilities of this chimeric receptor. Finally, we predicted the ability of these determinants to inform host range identification of preemergent coronaviruses by evaluating hot spot contacts between SARS-CoV-2 and additional potential host receptors. Our results identify residue determinants that mediate coronavirus receptor usage and host range for application in SARSCoV-2 and emerging coronavirus animal model development. IMPORTANCE SARS-CoV-2 (the causative agent of COVID-19) is a major public health threat and one of two related coronaviruses that have caused epidemics in modern history. A method of screening potential infectible hosts for preemergent and future emergent coronaviruses would aid in mounting rapid response and intervention strategies during future emergence events. Here, we evaluated determinants of SARS-CoV-2 receptor interactions, identifying key changes that enable or prevent infection. The analysis detailed in this study will aid in the development of model systems to screen emergent coronaviruses as well as treatments to counteract infections.

2.
Preprint in English | PubMed | ID: ppcovidwho-9016

ABSTRACT

Monoclonal antibodies (mAbs) with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefit in cases of mild to moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1-4. Treatment generally requires the administration of high doses of these mAbs with limited efficacy in preventing disease complications or mortality among hospitalized COVID-19 patients5. Here we report the development and evaluation of Fc-optimized anti-SARS-CoV-2 mAbs with superior potency to prevent or treat COVID-19 disease. In several animal models of COVID-19 disease6,7, we demonstrate that selective engagement of activating FcgammaRs results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection upon SARS-CoV-2 challenge and treatment of pre-infected animals. Our results highlight the importance of FcgammaR pathways in driving antibody-mediated antiviral immunity, while excluding any pathogenic or disease-enhancing effects of FcgammaR engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered mAbs with optimal Fc effector function and improved clinical efficacy against COVID-19 disease.

3.
Topics in Antiviral Medicine ; 29(1):135-136, 2021.
Article in English | EMBASE | ID: covidwho-1250916

ABSTRACT

Background: We previously showed that β-D-N4-hydroxycytidine (rNHC) and its orally bioavailable prodrug, molnupiravir, acts as a broad-spectrum antiviral against coronaviruses in vitro and in vivo through lethal mutagenesis. Molnupiravir is currently in clinical trials for the treatment of SARS-CoV-2 infection. However, there are concerns that rNHC could be metabolized to dNHC and cause mutations in host cells. We examined the in vitro antiviral and mammalian cell mutagenic activity of three different nucleoside/base analogs, rNHC, favipiravir, and ribavirin, on SARS-CoV-2. We further examined the in vitro genotoxicity of a panel of antiviral nucleotide/nucleoside analogs, including rNHC, using a modified HPRT gene mutation assay. Methods: A549-hACE2 cells were infected with SARS-CoV-2 in the presence of nucleoside analogs. After 48 hours, the supernatants were collected and viral RNA was extracted. We constructed multiplexed-Primer ID libraries from viral RNA and sequenced them using MiSeq. HPRT knockout assays were performed using CHO-K1 cells treated with a panel of nucleotide/nucleoside analogs for 32 days. After 6-thioguanine selection, resistant cell colonies were counted as a measure of HPRT knockout mutations in host cells, and HPRT mRNA was sequenced from selected colonies. Results: rNHC showed dose-dependent antiviral and mutagenic effects against SAR-CoV-2 in vitro. In the 10 μM group, we found 7-fold and 14-fold increases in the overall substitution rate and the C to U mutation rate, respectively. The HPRT assay showed an rNHC dose-dependent increase in the number of resistant colonies with HPRT gene mutations. Other analogs showed no significant increase in the number of 6-thioG resistant colonies except for a slight increase with favipiravir (Fig 1a). Most colonies had missense substitutions or frame-shift deletions within HPRT mRNA, with most being distinct. Conclusion: rNHC showed a dose-dependent inhibition and mutagenic effect of SAR-CoV-2 in vitro. However, rNHC would be expected to be metabolized into the deoxynucleotide pool (by host RNR), resulting in DNA mutation of dividing mammalian cells. We demonstrated such mutagenic potential in a simple mammalian cell detection scheme. Molnupiravir has considerable potential as an orally bioavailable direct acting antiviral against SARS-CoV2 early in infection, especially in high risk patients. However, clinical use should be carefully considered in light of its potential mutagenic effects on the host.

4.
Topics in Antiviral Medicine ; 29(1):304-305, 2021.
Article in English | EMBASE | ID: covidwho-1250563

ABSTRACT

Background: The emergence of SARS-CoV-2 viral variants threatens current anti-viral and preventative strategies, including monoclonal antibodies and vaccines. Critically, the limited supply of vaccines and the complex logistics surrounding the delivery of infusion-based therapies herald the need for an easily produced, distributed, and specific direct-acting antiviral for COVID-19 that limits progression of illness and ideally prevents transmission. Methods: The efficacy of molnupiravir was evaluated in a double-blind, randomized, placebo-controlled, Phase 2 dose-range finding study using realtime polymerase chain reaction (RT-PCR) and virus isolation was conducted at 11 study sites in the U.S. Participants were randomized if they had signs or symptoms of COVID-19 within 7 days, and a positive SARS-CoV-2 RT-PCR within 4 days of enrollment. Initially, participants were randomized in a 1:1 ratio to receive 200 mg molnupiravir or placebo twice daily for 5 days. Subsequently, in the dose-range finding portion of the study, participants were randomized in a 3:1 ratio to receive 200, 400, or 800 mg molnupiravir or placebo twice daily for 5 days. Nasopharyngeal swabs were analyzed from 175 subjects at enrollment, Day 3, and Day 5 for SARS-CoV-2 infectivity. Samples were stored at 4°C for up to 72 hours, shipped refrigerated, aliquoted, and stored at -80°C until testing. Vero E6 cell monolayers were infected with the sample for 1 hour. Culture medium was analyzed for viral load at 2 and 5 days post-infection by RT-PCR. Results: Seventy-eight (45%) participants, median 4.62 days (min. 1.40, max. 7.54) from symptom onset, had a positive SARS-CoV-2 culture at enrollment (52 on active and 26 on placebo). The percentage of participants with a positive viral culture at enrollment who were positive on Day 3 was 20.4% on active and 28% on placebo (p = 0.56). At day 5, 24% of placebo participants were culturethe positive compared to none treated with molnupiravir (p = 0.001). Between treatment, comparisons were performed using Fisher's exact test. Conclusion: This is the first demonstration of reduced infectiousness by antiviral therapy in people with SARS-2 infection. This simple, short-course oral therapy may benefit individuals and public health and is unlikely to be impacted by spike-protein variants.

5.
Epidemiol Infect ; 148: e267, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-912841

ABSTRACT

Previous research on respiratory infection transmission among university students has primarily focused on influenza. In this study, we explore potential transmission events for multiple respiratory pathogens in a social contact network of university students. University students residing in on-campus housing (n = 590) were followed for the development of influenza-like illness for 10-weeks during the 2012-13 influenza season. A contact network was built using weekly self-reported contacts, class schedules, and housing information. We considered a transmission event to have occurred if students were positive for the same pathogen and had a network connection within a 14-day period. Transmitters were individuals who had onset date prior to their infected social contact. Throat and nasal samples were analysed for multiple viruses by RT-PCR. Five viruses were involved in 18 transmission events (influenza A, parainfluenza virus 3, rhinovirus, coronavirus NL63, respiratory syncytial virus). Transmitters had higher numbers of co-infections (67%). Identified transmission events had contacts reported in small classes (33%), dormitory common areas (22%) and dormitory rooms (17%). These results suggest that targeting person-to-person interactions, through measures such as isolation and quarantine, could reduce transmission of respiratory infections on campus.


Subject(s)
Respiratory Tract Infections/virology , Social Networking , Students , Virus Diseases/transmission , Coinfection/virology , Female , Housing , Humans , Male , Michigan , Respiratory Tract Infections/transmission , Universities
6.
Eur Heart J ; 41(22): 2092-2112, 2020 06 07.
Article in English | MEDLINE | ID: covidwho-574867

ABSTRACT

The COVID-19 pandemic has greatly impacted the daily clinical practice of cardiologists and cardiovascular surgeons. Preparedness of health workers and health services is crucial to tackle the enormous challenge posed by SARS-CoV-2 in wards, operating theatres, intensive care units, and interventionist laboratories. This Clinical Review provides an overview of COVID-19 and focuses on relevant aspects on prevention and management for specialists within the cardiovascular field.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/transmission , Endocarditis/surgery , Humans , Male , Middle Aged , Pneumonia, Viral/diagnosis , Pneumonia, Viral/transmission , Prosthesis-Related Infections/surgery , SARS-CoV-2
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