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Viruses Feb 2024Monkeypox virus (MPXV), the pathogen responsible for the infectious disease monkeypox, causes lesions on the skin, lymphadenopathy, and fever. It has posed a global...
Monkeypox virus (MPXV), the pathogen responsible for the infectious disease monkeypox, causes lesions on the skin, lymphadenopathy, and fever. It has posed a global public health threat since May 2022. Highly sensitive and specific detection of MPXV is crucial for preventing the spread of the disease. Argonaute (Ago) is an artificial DNA-guided restriction cleavage enzyme programmable with 5'-phosphorylated ssDNA sequences, which can be developed to specifically detect nucleic acids of pathogens. Here, a Ago-based system was established for the detection of MPXV-specific DNA targeting the F3L gene. A short amplicon of 79 bp could be obtained through a fast PCR procedure, which was completed within 45 min. Two 5'-phosphorylation guide DNAs were designed to guide Ago to cleave the amplicon to obtain an 18 bp 5'-phosphorylation sequence specific to MPXV, not to other orthopoxviruses (cowpox, variola, and vaccinia viruses). The 18 bp sequence guided Ago to cleave a designed probe specific to MPXV to emit fluorescence. With optimized conditions for the Ago-MPXV system, it could be completed in 60 min for the detection of the extracted MPXV DNA with the limit of detection (LOD) of 1.1 copies/reaction and did not depend on expensive instruments. Successful application of the Ago-MPXV system in sensitively detecting MPXV in simulated throat swabs, skin swabs, sera, and wastewater demonstrated the system's good performance. The Ago platform, with high sensitivity and specificity established here, has the potential to prevent the spread of MPXV.
Topics: Humans; Mpox (monkeypox); Pyrococcus furiosus; Monkeypox virus; DNA; Argonaute Proteins
PubMed: 38543748
DOI: 10.3390/v16030382 -
Viruses Feb 2024The history of virology, which is marked by transformative breakthroughs, spans microbiology, biochemistry, genetics, and molecular biology. From the development of... (Review)
Review
The history of virology, which is marked by transformative breakthroughs, spans microbiology, biochemistry, genetics, and molecular biology. From the development of Jenner's smallpox vaccine in 1796 to 20th-century innovations such as ultrafiltration and electron microscopy, the field of virology has undergone significant development. In 1898, Beijerinck laid the conceptual foundation for virology, marking a pivotal moment in the evolution of the discipline. Advancements in influenza A virus research in 1933 by Richard Shope furthered our understanding of respiratory pathogens. Additionally, in 1935, Stanley's determination of viruses as solid particles provided substantial progress in the field of virology. Key milestones include elucidation of reverse transcriptase by Baltimore and Temin in 1970, late 20th-century revelations linking viruses and cancer, and the discovery of HIV by Sinoussi, Montagnier, and Gallo in 1983, which has since shaped AIDS research. In the 21st century, breakthroughs such as gene technology, mRNA vaccines, and phage display tools were achieved in virology, demonstrating its potential for integration with molecular biology. The achievements of COVID-19 vaccines highlight the adaptability of virology to global health.
Topics: Humans; COVID-19 Vaccines; Viruses; Molecular Biology; Neoplasms; Microscopy, Electron; Virology
PubMed: 38543740
DOI: 10.3390/v16030374 -
Microorganisms Mar 2024Viruses are minuscule infectious agents that reproduce exclusively within the living cells of an organism and are present in almost every ecosystem. Their continuous... (Review)
Review
Viruses are minuscule infectious agents that reproduce exclusively within the living cells of an organism and are present in almost every ecosystem. Their continuous interaction with humans poses a significant threat to the survival and well-being of everyone. Apart from the common cold or seasonal influenza, viruses are also responsible for several important diseases such as polio, rabies, smallpox, and most recently COVID-19. Besides the loss of life and long-term health-related issues, clinical viral infections have significant economic and social impacts. Viral enzymes, especially proteases which are essential for viral multiplication, represent attractive drug targets. As a result, screening of viral protease inhibitors has gained a lot of interest in the development of anti-viral drugs. Despite the availability of anti-viral therapeutics, there is a clear need to develop novel curative agents that can be used against a given virus or group of related viruses. This review highlights the importance of yeasts as an in vivo model for screening viral enzyme inhibitors. We also discuss the advantages of yeast-based screening platforms over traditional assays. Therefore, in the present article, we discuss why yeast is emerging as a model of choice for in vivo screening of anti-viral molecules and why yeast-based screening will become more relevant in the future for screening anti-viral and other molecules of clinical importance.
PubMed: 38543629
DOI: 10.3390/microorganisms12030578 -
Signal Transduction and Targeted Therapy Mar 2024The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic...
The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production. Herein, by using the established lipid nanoparticle (LNP)-encapsulated mRNA platform, we constructed four mRNA combinations that encode monoclonal antibodies with broad neutralization activities against orthopoxviruses. In vivo characterization demonstrated that a single intravenous injection of each LNP-encapsulated mRNA antibody in mice resulted in the rapid production of neutralizing antibodies. More importantly, mRNA antibody treatments showed significant protection from weight loss and mortality in the vaccinia virus (VACV) lethal challenge mouse model, and a unique mRNA antibody cocktail, Mix2a, exhibited superior in vivo protection by targeting both intracellular mature virus (IMV)-form and extracellular enveloped virus (EEV)-form viruses. In summary, our results demonstrate the proof-of-concept production of orthopoxvirus antibodies via the LNP-mRNA platform, highlighting the great potential of tailored mRNA antibody combinations as a universal strategy to combat orthopoxvirus as well as other emerging viruses.
Topics: Animals; Mice; Orthopoxvirus; Combined Antibody Therapeutics; Vaccinia; Antibodies, Viral; Vaccinia virus
PubMed: 38531869
DOI: 10.1038/s41392-024-01766-8 -
Open Forum Infectious Diseases Mar 2024We conducted a multicentric national study (SEIMC-CEME-22), to describe the clinical and epidemiological profile of the mpox outbreak in Spain, including the management...
BACKGROUND
We conducted a multicentric national study (SEIMC-CEME-22), to describe the clinical and epidemiological profile of the mpox outbreak in Spain, including the management of the disease.
METHODS
This was a retrospective national observational study conducted by Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) and Foundation SEIMC-GESIDA. We included patients with a confirmed mpox diagnosis before 13 July 2022, and attended at the Spanish health network (the early phase of the outbreak). Epidemiological, clinical, and therapeutic data were collected.
RESULTS
Of a total of 1472 patients from 52 centers included, 99% of them were cisgender men, mostly middle-aged, and 98.6% were residents in Spain. The main suspected route of transmission was sexual exposure, primarily among MSM. Occupational exposure was reported in 6 patients. Immunosuppression was present in 40% of patients, mainly due to human immunodeficiency virus (HIV). Only 6.5% of patients had been vaccinated against orthopoxvirus. Virus sequencing was performed in 147 patients (all B.1 lineage). Rash was the most frequent symptom (95.7%), followed by fever (48.2%), adenopathies (44.4%) myalgias (20.7%), proctitis (17%), and headache (14.7%). Simultaneously diagnosed sexually transmitted infections included syphilis (n = 129), gonococcal infection (n = 91), HIV (n = 67), chlamydia (n = 56), hepatitis B (n = 14), and hepatitis C (n = 11). No therapy was used in 479 patients (33%). Symptomatic therapies and antibiotics were used in 50% of cases. The most used therapy regimens were systemic corticoids (90 patients), tecovirimat (6 patients), and cidofovir (13 patients). Smallpox immunoglobulins were used in 1 patient. Fifty-eight patients were hospitalized, and 1 patient died.
CONCLUSIONS
Mpox outbreak in Spain affected primarily middle-aged men who were sexually active and showed a high rate of HIV infection. A range of heterogeneous therapeutics options was performed.
PubMed: 38524223
DOI: 10.1093/ofid/ofae105 -
Human Vaccines & Immunotherapeutics Dec 2024This phase-3, double-blind, placebo-controlled study (NCT04228783) evaluated lot-to-lot consistency of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. Participants... (Randomized Controlled Trial)
Randomized Controlled Trial
Lot-to-lot consistency, immunogenicity, and safety of the Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen: A phase 3, randomized, double-blind, placebo-controlled trial.
This phase-3, double-blind, placebo-controlled study (NCT04228783) evaluated lot-to-lot consistency of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. Participants were randomized (6:6:6:1) to receive the two-dose regimen from three consecutively manufactured lots of Ad26.ZEBOV on Day 1 paired with three consecutively manufactured lots of MVA-BN-Filo on Day 57 (Groups 1-3) or two doses of placebo (Group 4). An additional cohort also received an Ad26.ZEBOV booster or placebo 4 months post-dose 2. Equivalence of the immunogenicity at 21 days post-dose 2 between any two groups was demonstrated if the 95% confidence interval (CI) of the Ebola virus glycoprotein (EBOV GP)-binding antibody geometric mean concentration (GMC) ratio was entirely within the prespecified margin of 0.5-2.0. Lot-to-lot consistency (i.e., consecutive lots can be consistently manufactured) was accomplished if equivalence was shown for all three pairwise comparisons. Results showed that the primary objective in the per-protocol immunogenicity subset ( = 549) was established for each pairwise comparison (Group 1 vs 2: GMC ratio = 0.9 [95% CI: 0.8, 1.1], Group 1 vs 3: 0.9 [0.8, 1.1], Group 2 vs 3: 1.0 [0.9, 1.2]). Equivalence of the three groups for the Ad26.ZEBOV component only was also demonstrated at 56 days post-dose 1. EBOV GP-binding antibody responses (post-vaccination concentrations >2.5-fold from baseline) were observed in 419/421 (99.5%) vaccine recipients at 21 days post-dose 2 and 445/460 (96.7%) at 56 days post-dose 1. In the booster cohort ( = 39), GMCs increased 9.0- and 11.8-fold at 7 and 21 days post-booster, respectively, versus pre-booster. Ad26.ZEBOV, MVA-BN-Filo was well tolerated, and no safety issues were identified.
Topics: Humans; Ebola Vaccines; Hemorrhagic Fever, Ebola; Ebolavirus; Vaccination; Antibodies, Viral; Double-Blind Method; Immunogenicity, Vaccine; Smallpox Vaccine; Vaccines, Attenuated
PubMed: 38523332
DOI: 10.1080/21645515.2024.2327747 -
Emerging Microbes & Infections Dec 2024Generating an infectious non-human primate (NHP) model using a prevalent monkeypox virus (MPXV) strain has emerged as a crucial strategy for assessing the efficacy of...
Generating an infectious non-human primate (NHP) model using a prevalent monkeypox virus (MPXV) strain has emerged as a crucial strategy for assessing the efficacy of vaccines and antiviral drugs against human MPXV infection. Here, we established an animal model by infecting cynomolgus macaques with the prevalent MPXV strain, WIBP-MPXV-001, and simulating its natural routes of infection. A comprehensive analysis and evaluation were conducted on three animals, including monitoring clinical symptoms, collecting hematology data, measuring viral loads, evaluating cellular and humoral immune responses, and examining histopathology. Our findings revealed that initial skin lesions appeared at the inoculation sites and subsequently spread to the limbs and back, and all infected animals exhibited bilateral inguinal lymphadenopathy, eventually leading to a self-limiting disease course. Viral DNA was detected in post-infection blood, nasal, throat, rectal and blister fluid swabs. These observations indicate that the NHP model accurately reflects critical clinical features observed in human MPXV infection. Notably, the animals displayed clinical symptoms and disease progression similar to those of humans, rather than a lethal outcome as observed in previous studies. Historically, MPXV was utilized as a surrogate model for smallpox. However, our study contributes to a better understanding of the dynamics of current MPXV infections while providing a potential infectious NHP model for further evaluation of vaccines and antiviral drugs against mpox infection. Furthermore, the challenge model closely mimics the primary natural routes of transmission for human MPXV infections. This approach enhances our understanding of the precise mechanisms underlying the interhuman transmission of MPXV.
Topics: Animals; Humans; Monkeypox virus; Mpox (monkeypox); Vaccines; Antiviral Agents; Macaca
PubMed: 38494777
DOI: 10.1080/22221751.2024.2332669 -
Annals of Medicine and Surgery (2012) Mar 2024Human monkeypox, caused by the monkeypox virus (MPXV), is an emerging infectious disease with the potential for human-to-human transmission and diverse clinical... (Review)
Review
Human monkeypox, caused by the monkeypox virus (MPXV), is an emerging infectious disease with the potential for human-to-human transmission and diverse clinical presentations. While generally considered milder than smallpox, it can lead to severe cardiovascular complications. The virus primarily spreads through contact with infected animals or through human-to-human transmission. Cardiovascular involvement in human monkeypox is rare but has been associated with myocarditis, pericarditis, arrhythmias, and even fulminant myocardial infarction. Vaccination plays a crucial role in preventing and controlling monkeypox, but the eradication of smallpox has left global populations vulnerable. This review explores the cardiovascular manifestations of human monkeypox, the role of vaccination in disease prevention, and the importance of continued research and development of effective vaccines to protect against this emerging infectious threat. The global impact of monkeypox outbreaks, particularly on vulnerable populations, further highlights the importance of understanding and addressing this disease.
PubMed: 38463133
DOI: 10.1097/MS9.0000000000001674 -
Cell Reports Mar 2024Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection and is a...
Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection and is a restriction factor for VACV and herpes simplex virus type 1. Here, we report that HDAC5 promotes interferon regulatory factor 3 (IRF3) activation downstream of Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 or Sendai virus-mediated stimulation without requiring HDAC activity. Loss of HDAC5-mediated IRF3 activation is restored by re-introduction of HDAC5 but not HDAC1 or HDAC4. The antiviral activity of HDAC5 is antagonized by VACV protein C6 and orthologs from the orthopoxviruses cowpox, rabbitpox, camelpox, monkeypox, and variola. Infection by many of these viruses induces proteasomal degradation of HDAC5, and expression of C6 alone can induce HDAC5 degradation. Mechanistically, C6 binds to the dimerization domain of HDAC5 and prevents homodimerization and heterodimerization with HDAC4. Overall, this study describes HDAC5 as a positive regulator of IRF3 activation and provides mechanistic insight into how the poxviral protein C6 binds to HDAC5 to antagonize its function.
Topics: Monkeypox virus; Variola virus; Orthopoxvirus; Interferon Regulatory Factor-3; Vaccinia virus; Histone Deacetylases
PubMed: 38461415
DOI: 10.1016/j.celrep.2024.113788 -
Journal of Korean Medical Science Mar 2024In response to the Mpox domestic epidemic, South Korea initiated a nationwide vaccination program in May 2023, administering a 0.1 mL intradermal dose of JYNNEOS...
In response to the Mpox domestic epidemic, South Korea initiated a nationwide vaccination program in May 2023, administering a 0.1 mL intradermal dose of JYNNEOS (Modified Vaccinia Ankara vaccine, Bavarian Nordic) to a high-risk group. To investigate the adverse reactions after intradermal JYNNEOS vaccination, an anonymous online survey was conducted at the National Medical Center from May 22 to July 31, 2023. Overall, 142 individuals responded. Over 80% of the respondents reported local reactions of predominantly mild severity. The predominant local reactions were pruritus, redness, and swelling; their incidence rates after the first dose were 66.2%, 48.1%, and 49.4%, respectively; the corresponding rates after the second dose were 69.2%, 60.6%, and 53.8%. Fewer respondents reported systemic symptoms. The most common systemic symptom was fatigue, the incidence rates of which after the first and second doses were 37.7% and 24.6%, respectively. Overall, the intradermally administered JYNNEOS vaccine appeared well tolerated.
Topics: Humans; Mpox (monkeypox); Republic of Korea; Vaccination; Vaccines; Smallpox Vaccine; Injections, Intradermal
PubMed: 38442725
DOI: 10.3346/jkms.2024.39.e100