scholarly journals Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wen Juan Tu ◽  
Robert D. McCuaig ◽  
Michelle Melino ◽  
Daniel J. Rawle ◽  
Thuy T. Le ◽  
...  
Keyword(s):  
Viral Replication ◽  
Treatment Options ◽  
Critical Role ◽  
Post Exposure Prophylaxis ◽  
Nuclear Entry ◽  
Importin Α ◽  
Active Transcription ◽  
Nuclear Shuttling ◽  
Asymptomatic Phase ◽  
Exposure Prophylaxis

AbstractTreatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

scholarly journals The nucleocapsid protein of rice stripe virus in cell nuclei of vector insect regulates viral replication

2021 ◽  
Author(s):  
Wan Zhao ◽  
Junjie Zhu ◽  
Hong Lu ◽  
Jiaming Zhu ◽  
Fei Jiang ◽  
...  
Keyword(s):  
Viral Replication ◽  
Nucleocapsid Protein ◽  
Brown Planthopper ◽  
Rice Stripe Virus ◽  
Host Cells ◽  
Cell Nuclei ◽  
Nuclear Entry ◽  
Genomic Rnas ◽  
Importin Α ◽  
Vector Insect

AbstractRice stripe virus (RSV) transmitted by the small brown planthopper causes severe rice yield losses in Asian countries. Although viral nuclear entry promotes viral replication in host cells, whether this phenomenon occurs in vector cells remains unknown. Therefore, in this study, we systematically evaluated the presence and roles of RSV in the nuclei of vector insect cells. We observed that the nucleocapsid protein (NP) and viral genomic RNAs were partially transported into vector cell nuclei by utilizing the importin α nuclear transport system. When blocking NP nuclear localization, cytoplasmic RSV accumulation significantly increased. In the vector cell nuclei, NP bound the transcription factor YY1 and affected its positive regulation to FAIM. Subsequently, decreased FAIM expression triggered an antiviral caspase-dependent apoptotic reaction. Our results reveal that viral nuclear entry induces completely different immune effects in vector and host cells, providing new insights into the balance between viral load and the immunity pressure in vector insects.

scholarly journals Current Status and Trends in Prophylaxis and Management of Anthrax Disease

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 370 ◽  
Author(s):  
Vladimir Savransky ◽  
Boris Ionin ◽  
Joshua Reece
Keyword(s):  
Treatment Options ◽  
Clinical Manifestations ◽  
World Health ◽  
Current Status ◽  
Post Exposure Prophylaxis ◽  
Mortality And Morbidity ◽  
Symptomatic Disease ◽  
Prevention And Treatment ◽  
Health Organization ◽  
Exposure Prophylaxis

Bacillus anthracis has been identified as a potential military and bioterror agent as it is relatively simple to produce, with spores that are highly resilient to degradation in the environment and easily dispersed. These characteristics are important in describing how anthrax could be used as a weapon, but they are also important in understanding and determining appropriate prevention and treatment of anthrax disease. Today, anthrax disease is primarily enzootic and found mostly in the developing world, where it is still associated with considerable mortality and morbidity in humans and livestock. This review article describes the spectrum of disease caused by anthrax and the various prevention and treatment options. Specifically we discuss the following; (1) clinical manifestations of anthrax disease (cutaneous, gastrointestinal, inhalational and intravenous-associated); (2) immunology of the disease; (3) an overview of animal models used in research; (4) the current World Health Organization and U.S. Government guidelines for investigation, management, and prophylaxis; (5) unique regulatory approaches to licensure and approval of anthrax medical countermeasures; (6) the history of vaccination and pre-exposure prophylaxis; (7) post-exposure prophylaxis and disease management; (8) treatment of symptomatic disease through the use of antibiotics and hyperimmune or monoclonal antibody-based antitoxin therapies; and (9) the current landscape of next-generation product candidates under development.

scholarly journals 150. Updated Clinical Guidelines for Treatment and Prophylaxis of Plague

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S91-S91
Author(s):  
Christina Nelson ◽  
Katharine Cooley ◽  
Shannon Fleck-Derderian
Keyword(s):  
Clinical Guidelines ◽  
Early Recognition ◽  
Treatment Options ◽  
Antimicrobial Treatment ◽  
Post Exposure Prophylaxis ◽  
First Line ◽  
Effective Response ◽  
Animal Data ◽  
Bioterrorism Agent ◽  
Exposure Prophylaxis

Abstract Background Plague still occurs naturally in the western United States, Latin America, Asia, and Africa. Yersinia pestis, the causative agent of plague, is a Tier 1 bioterrorism agent due to its potential for aerosol release and high fatality rates. Recommendations for treatment and post-exposure prophylaxis (PEP) of plague were published in 2000 and included limited first-line options for treating plague, namely streptomycin or gentamicin. Doxycycline or ciprofloxacin were recommended for PEP. However, since 2000 new human clinical data and animal data have become available, and the FDA has approved additional antimicrobials for plague. Methods CDC developed updated, evidence-based guidelines for treatment and prophylaxis of plague using a comprehensive process. To collect evidence on relative efficacy of various antimicrobials for treatment of plague, the guidelines team conducted systematic literature reviews and analyzed U.S. surveillance data. Results of these investigations were published in Clinical Infectious Diseases in 2020. We also hosted several meetings with subject matter experts and clinical organizations (IDSA, AAP, etc.), federal agencies, and others to review relevant data and gather individual input on treatment and prophylaxis of plague. Results The forthcoming plague guidelines will include several important updates. First-line treatment options have been expanded to include ciprofloxacin, levofloxacin, and moxifloxacin in addition to streptomycin and gentamicin. For PEP, levofloxacin and moxifloxacin are now first-line options in addition to doxycycline and ciprofloxacin. Trimethoprim-sulfamethoxazole is now one of several new alternative options for PEP. The updated guidelines also include recommendations for treatment of clinical forms of plague other than pneumonic. Additional special populations such as immunocompromised persons and neonates are also covered. Conclusion Plague remains a threat, both as a naturally occurring disease and as a potential bioterrorism weapon, and preparedness and early recognition are key to effective response. The updated clinical guidelines will be a useful tool for clinicians to manage antimicrobial treatment and PEP for plague. Disclosures All Authors: No reported disclosures

scholarly journals Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics

2014 ◽  
Vol 25 (16) ◽  
pp. 2472-2484 ◽  
Author(s):  
Abigail L. Buchwalter ◽  
Yun Liang ◽  
Martin W. Hetzer
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Nuclear Pore ◽  
Binding Domains ◽  
Importin Α ◽  
Transcription Regulators ◽  
Active Transcription ◽  
Chromatin Biology

The nuclear pore complex (NPC) plays a critical role in gene expression by mediating import of transcription regulators into the nucleus and export of RNA transcripts to the cytoplasm. Emerging evidence suggests that in addition to mediating transport, a subset of nucleoporins (Nups) engage in transcriptional activation and elongation at genomic loci that are not associated with NPCs. The underlying mechanism and regulation of Nup mobility on and off nuclear pores remain unclear. Here we show that Nup50 is a mobile Nup with a pronounced presence both at the NPC and in the nucleoplasm that can move between these different localizations. Strikingly, the dynamic behavior of Nup50 in both locations is dependent on active transcription by RNA polymerase II and requires the N-terminal half of the protein, which contains importin α– and Nup153-binding domains. However, Nup50 dynamics are independent of importin α, Nup153, and Nup98, even though the latter two proteins also exhibit transcription-dependent mobility. Of interest, depletion of Nup50 from C2C12 myoblasts does not affect cell proliferation but inhibits differentiation into myotubes. Taken together, our results suggest a transport-independent role for Nup50 in chromatin biology that occurs away from the NPC.

Low awareness and use of post-exposure prophylaxis among adolescents and young adults in South Africa: implications for the prevention of new HIV infections

2020 ◽  
Vol 19 (3) ◽  
pp. 242-248
Author(s):  
Anthony Idowu Ajayi ◽  
Mohammed Sanusi Yusuf ◽  
Elmon Mudefi ◽  
Oladele Vincent Adeniyi ◽  
Ntombana Rala ◽  
...  
Keyword(s):  
South Africa ◽  
Young Adults ◽  
Hiv Infections ◽  
Adolescents And Young Adults ◽  
Post Exposure Prophylaxis ◽  
Post Exposure ◽  
Exposure Prophylaxis

Study of sharp injuries and blood splash exposures among healthcare workers in a tertiary hospital in Bangalore

2016 ◽  
Vol 12 (3) ◽  
Author(s):  
Shalini Sivananjiah Pradeep ◽  
Suman Gadicherla Raghu ◽  
Prathab A G ◽  
Banashankari G Rudresh ◽  
Radhika Kunnavil
Keyword(s):  
Healthcare Workers ◽  
Tertiary Hospital ◽  
Post Exposure Prophylaxis ◽  
Care Hospital ◽  
Post Exposure ◽  
Increased Risk ◽  
Management Procedures ◽  
Exposure Prophylaxis ◽  
Sharps Injury ◽  
Sharps Injuries

The working environment of healthcare workers (HCW) exposes them to sharp injuries. This communication attempts to examine the injury registers, incidence of sharps injuries and blood splash exposures, and the post-exposure prophylaxis status of employees in a tertiary care hospital. Analysis included records form 54 locations of two units of a tertiary hospital attached to a Medical College. Maintenance of the injury register overall was highly satisfactory in both units. Two hundred and nine injuries were recorded from both units of the hospital. The majority of injuries (60.5%) occurred in the age group of 20-30 years with 70% among females. Waste handlers were at increased risk during waste management procedures. Thirty two percent of sharps injury injuries occurred in wards. Of the ward nursing staff, 25.3% received sharps injuries. Post-exposure prophylaxis for Hepatitis B (primary dose) was given to 25 HCWs; 11 received booster doses. The basic regimen for HIV post-exposure prophylaxis was given to 4 HCWs. Awareness about records maintenance, regular documentation, awareness and training, and implementation of appropriate preventive measures can reduce the incidence of injuries. Key words: Sharps, injury register, Health care workers (HCW),Post exposure prophylaxis (PEP)

Efficacy of one-dose intramuscular rabies vaccine as pre-exposure prophylaxis in travellers

2021 ◽  
Author(s):  
Deborah J Mills ◽  
Colleen L Lau ◽  
Christine Mills ◽  
Luis Furuya-Kanamori
Keyword(s):  
Immune System ◽  
Rapid Development ◽  
Age Groups ◽  
Rabies Vaccine ◽  
Post Exposure Prophylaxis ◽  
Post Intervention ◽  
Quasi Experimental ◽  
Alternative Schedule ◽  
Insufficient Time ◽  
Exposure Prophylaxis

Abstract Background Current guidelines for rabies pre-exposure prophylaxis (PrEP) recommend multiple vaccine doses. Travellers sometimes present for pre-travel consultation with insufficient time to complete standard PrEP schedules. We investigated the efficacy of one-dose intramuscular (IM) vaccine in priming the immune system (as PrEP) by measuring antibody response to simulated post-exposure prophylaxis (PEP). Methods A quasi-experimental pre–post intervention clinical trial was conducted at a specialist travel clinic in Australia. Adults (≥18 years) without a history of rabies vaccination were included. At Visit 1, seronegative status was confirmed and one dose of 0.5 ml IM rabies vaccine (Verorab®) administered. At Visit 2 (≥60 days after Visit 1), serology was repeated and a simulated PEP dose (0.5 ml IM) given on this day and again 3 days later (Visit 3). Serology was repeated at Visit 4 (7 days after Visit 2). Results A total of 94 antibody-negative participants were included (<50 years [n = 50]; ≥50 years [n = 44]). At Visit 2, 38.0 and 31.8% of participants aged <50 and ≥50 years were antibody-positive (≥0.5 EU/ml). At Visit 4, all participants were antibody-positive; 82.0 and 47.7% of participants aged <50 and ≥50 years had antibody levels >4 EU/ml, respectively. Conclusions One-dose IM vaccine was effective as PrEP for priming the immune system in both age groups, resulting in rapid development of antibodies 7 days after commencing simulated PEP. If there is insufficient time to complete a standard PrEP schedule, one-dose IM could be considered as an alternative schedule for short trips, rather than not offering travellers any doses at all. Clinical trials registration: ACTRN12619000946112.

scholarly journals 986. Improvement in Administration of HIV Post-Exposure Prophylaxis in the Emergency Department Following Sexual Assault

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S521-S522
Author(s):  
Jennifer R Silva-Nash ◽  
Stacie Bordelon ◽  
Ryan K Dare ◽  
Sherrie Searcy
Keyword(s):  
Emergency Department ◽  
Sexual Assault ◽  
Hiv Transmission ◽  
Post Exposure Prophylaxis ◽  
Intervention Period ◽  
Post Intervention ◽  
Post Exposure ◽  
Assault Victims ◽  
Exposure Prophylaxis

Abstract Background Nonoccupational post exposure prophylaxis (nPEP) following sexual assault can prevent HIV transmission. A standardized Emergency Department (ED) protocol for evaluation, treatment, and follow up for post assault victims was implemented to improve compliance with CDC nPEP guidelines. Methods A single-center observational study of post sexual assault patients before/after implementation of an ED nPEP protocol was conducted by comparing the appropriateness of prescriptions, labs, and necessary follow up. A standardized order-set based on CDC nPEP guidelines, with involvement of an HIV pharmacist and ID clinic, was implemented during the 2018-2019 academic year. Clinical data from pre-intervention period (07/2016-06/2017) was compared to post-intervention period (07/2018-08/2019) following a 1-year washout period. Results During the study, 147 post-sexual assault patients (59 Pre, 88 Post) were included. One hundred thirty-three (90.4%) were female, 68 (46.6%) were African American and 133 (90.4%) were candidates for nPEP. Median time to presentation following assault was 12.6 hours. nPEP was offered to 40 (67.8%) and 84 (95.5%) patients (P< 0.001) and ultimately prescribed to 29 (49.2%) and 71 (80.7%) patients (P< 0.001) in pre and post periods respectively. Renal function (37.3% vs 88.6%; P< 0.001), pregnancy (39.0% vs 79.6%; P< 0.001), syphilis (3.4% vs 89.8%; P< 0.001), hepatitis B (15.3% vs 95.5%; P< 0.001) and hepatitis C (27.1% vs 94.3%) screening occurred more frequently during the post period. Labratory, nPEP Prescription and Follow up Details for Patients Prescribed nPEP Conclusion The standardization of an nPEP ED protocol for sexual assault victims resulted in increased nPEP administration, appropriateness of prescription, screening for other sexually transmitted infectious and scheduling follow up care. While guideline compliance dramatically improved, further interventions are likely warranted in this vulnerable population. Disclosures Ryan K. Dare, MD, MS, Accelerate Diagnostics, Inc (Research Grant or Support)

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