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Infectious Diseases of Poverty Nov 2023Mosquito research in Europe has a long history, primarily focused on malaria vectors. In recent years, invasive mosquito species like the Asian tiger mosquito (Aedes...
BACKGROUND
Mosquito research in Europe has a long history, primarily focused on malaria vectors. In recent years, invasive mosquito species like the Asian tiger mosquito (Aedes albopictus) and the spread of arboviruses like dengue virus, chikungunya virus or bluetongue virus have led to an intensification of research and monitoring in Europe. The risk of further dissemination of exotic species and mosquito-borne pathogens is expected to increase with ongoing globalization, human mobility, transport geography, and climate warming. Researchers have conducted various studies to understand the ecology, biology, and effective control strategies of mosquitoes and associated pathogens.
MAIN BODY
Three invasive mosquito species are established in Europe: Asian tiger mosquito (Aedes albopictus), Japanese bush mosquito (Ae. japonicus), and Korean bush mosquito (Aedes koreicus). Ae. albopictus is the most invasive species and has been established in Europe since 1990. Over the past two decades, there has been an increasing number of outbreaks of infections by mosquito-borne viruses in particular chikungunya virus, dengue virus or Zika virus in Europe primary driven by Ae. albopictus. At the same time, climate change with rising temperatures results in increasing threat of invasive mosquito-borne viruses, in particular Usutu virus and West Nile virus transmitted by native Culex mosquito species. Effective mosquito control programs require a high level of community participation, going along with comprehensive information campaigns, to ensure source reduction and successful control. Control strategies for container breeding mosquitoes like Ae. albopictus or Culex species involve community participation, door-to-door control activities in private areas. Further measures can involve integration of sterile insect techniques, applying indigenous copepods, Wolbachia sp. bacteria, or genetically modified mosquitoes, which is very unlike to be practiced as standard method in the near future.
CONCLUSIONS
Climate change and globalization resulting in the increased establishment of invasive mosquitoes in particular of the Asian tiger mosquito Ae. albopictus in Europe within the last 30 years and increasing outbreaks of infections by mosquito-borne viruses warrants intensification of research and monitoring. Further, effective future mosquito control programs require increase in intense community and private participation, applying physical, chemical, biological, and genetical control activities.
Topics: Animals; Humans; Arboviruses; Introduced Species; Europe; Mosquito Vectors; Aedes; Zika Virus; Zika Virus Infection; Mosquito Control
PubMed: 38037192
DOI: 10.1186/s40249-023-01167-z -
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 -
Nature Communications Oct 2023Whether CD8 T lymphocytes control human immunodeficiency virus infection by cytopathic or non-cytopathic mechanisms is not fully understood. Multiple studies highlighted...
Whether CD8 T lymphocytes control human immunodeficiency virus infection by cytopathic or non-cytopathic mechanisms is not fully understood. Multiple studies highlighted non-cytopathic effects, but one hypothesis is that cytopathic effects of CD8 T cells occur before viral production. Here, to examine the role of CD8 T cells prior to virus production, we treated SIVmac251-infected macaques with an integrase inhibitor combined with a CD8-depleting antibody, or with either reagent alone. We analyzed the ensuing viral dynamics using a mathematical model that included infected cells pre- and post- viral DNA integration to compare different immune effector mechanisms. Macaques receiving the integrase inhibitor alone experienced greater viral load decays, reaching lower nadirs on treatment, than those treated also with the CD8depleting antibody. Models including CD8 cell-mediated reduction of viral production (non-cytolytic) were found to best explain the viral profiles across all macaques, in addition an effect in killing infected cells pre-integration (cytolytic) was supported in some of the best models. Our results suggest that CD8 T cells have both a cytolytic effect on infected cells before viral integration, and a direct, non-cytolytic effect by suppressing viral production.
Topics: Humans; Animals; CD8-Positive T-Lymphocytes; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Macaca mulatta; Integrase Inhibitors; Viral Load; Virus Replication
PubMed: 37863982
DOI: 10.1038/s41467-023-42435-8 -
MBio May 2024The integration of HPV DNA into human chromosomes plays a pivotal role in the onset of papillomavirus-related cancers. HPV DNA integration often occurs by linearizing...
UNLABELLED
The integration of HPV DNA into human chromosomes plays a pivotal role in the onset of papillomavirus-related cancers. HPV DNA integration often occurs by linearizing the viral DNA in the E1/E2 region, resulting in the loss of a critical viral early polyadenylation signal (PAS), which is essential for the polyadenylation of the E6E7 bicistronic transcripts and for the expression of the viral E6 and E7 oncogenes. Here, we provide compelling evidence that, despite the presence of numerous integrated viral DNA copies, virus-host fusion transcripts originate from only a single integrated HPV DNA in HPV16 and HPV18 cervical cancers and cervical cancer-derived cell lines. The host genomic elements neighboring the integrated HPV DNA are critical for the efficient expression of the viral oncogenes that leads to clonal cell expansion. The fusion RNAs that are produced use a host RNA polyadenylation signal downstream of the integration site, and almost all involve splicing to host sequences. In cell culture, siRNAs specifically targeting the host portion of the virus-host fusion transcripts effectively silenced viral E6 and E7 expression. This, in turn, inhibited cell growth and promoted cell senescence in HPV16+ CaSki and HPV18+ HeLa cells. Showing that HPV E6 and E7 expression from a single integration site is instrumental in clonal cell expansion sheds new light on the mechanisms of HPV-induced carcinogenesis and could be used for the development of precision medicine tailored to combat HPV-related malignancies.
IMPORTANCE
Persistent oncogenic HPV infections lead to viral DNA integration into the human genome and the development of cervical, anogenital, and oropharyngeal cancers. The expression of the viral E6 and E7 oncogenes plays a key role in cell transformation and tumorigenesis. However, how E6 and E7 could be expressed from the integrated viral DNA which often lacks a viral polyadenylation signal in the cancer cells remains unknown. By analyzing the integrated HPV DNA sites and expressed HPV RNAs in cervical cancer tissues and cell lines, we show that HPV oncogenes are expressed from only one of multiple chromosomal HPV DNA integrated copies. A host polyadenylation signal downstream of the integrated viral DNA is used for polyadenylation and stabilization of the virus-host chimeric RNAs, making the oncogenic transcripts targetable by siRNAs. This observation provides further understanding of the tumorigenic mechanism of HPV integration and suggests possible therapeutic strategies for the development of precision medicine for HPV cancers.
Topics: Humans; Female; Uterine Cervical Neoplasms; Virus Integration; Oncogene Proteins, Viral; Papillomavirus Infections; DNA, Viral; Human papillomavirus 16; Human papillomavirus 18; Cell Line, Tumor; Oncogenes; Polyadenylation
PubMed: 38624210
DOI: 10.1128/mbio.00729-24 -
Molecular Therapy : the Journal of the... Oct 2023Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated....
Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated. Onasemnogene abeparvovec is an adeno-associated virus serotype 9-based gene therapy that improves survival, motor function, and motor milestone achievement in symptomatic and presymptomatic patients. Although the adeno-associated virus genome is maintained as an episome, theoretical risk of tumorigenicity persists should genomic insertion occur. We present the case of a 16-month-old male with spinal muscular atrophy who was diagnosed with an epithelioid neoplasm of the spinal cord approximately 14 months after receiving onasemnogene abeparvovec. In situ hybridization analysis detected an onasemnogene abeparvovec nucleic acid signal broadly distributed in many but not all tumor cells. Integration site analysis on patient formalin-fixed, paraffin-embedded tumor samples failed to detect high-confidence integration sites of onasemnogene abeparvovec. The finding was considered inconclusive because of limited remaining tissue/DNA input. The improved life expectancy resulting from innovative spinal muscular atrophy therapies, including onasemnogene abeparvovec, has created an opportunity to analyze the long-term adverse events and durability of these therapies as well as identify potential disease associations that were previously unrecognized because of the premature death of these patients.
PubMed: 37598295
DOI: 10.1016/j.ymthe.2023.08.013 -
Phytomedicine : International Journal... Jan 2024Esophageal squamous cell carcinoma (ESCC) is an aggressive and deadly malignancy characterized by late-stage diagnosis, therapy resistance, and a poor 5-year survival...
BACKGROUND
Esophageal squamous cell carcinoma (ESCC) is an aggressive and deadly malignancy characterized by late-stage diagnosis, therapy resistance, and a poor 5-year survival rate. Finding novel therapeutic targets and their inhibitors for ESCC prevention and therapy is urgently needed.
METHODS
We investigated the proviral integration site for maloney murine leukemia virus 3 (Pim-3) protein levels using immunohistochemistry. Using Methyl Thiazolyl Tetrazolium and clone formation assay, we verified the function of Pim-3 in cell proliferation. The binding and inhibition of Pim-3 by corynoline were verified by computer docking, pull-down assay, cellular thermal shift assay, and kinase assay. Cell proliferation, Western blot, and a patient-derived xenograft tumor model were performed to elucidate the mechanism of corynoline inhibiting ESCC growth.
RESULTS
Pim-3 was highly expressed in ESCC and played an oncogenic role. The augmentation of Pim-3 enhanced cell proliferation and tumor development by phosphorylating mitogen-activated protein kinase 1 (MAPK1) at T185 and Y187. The deletion of Pim-3 induced apoptosis with upregulated cleaved caspase-9 and lower Bcl2 associated agonist of cell death (BAD) phosphorylation at S112. Additionally, binding assays demonstrated corynoline directly bound with Pim-3, inhibiting its activity, and suppressing ESCC growth.
CONCLUSIONS
Our findings suggest that Pim-3 promotes ESCC progression. Corynoline inhibits ESCC progression through targeting Pim-3.
Topics: Animals; Mice; Humans; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Cell Movement; Apoptosis; Berberine Alkaloids
PubMed: 38128397
DOI: 10.1016/j.phymed.2023.155235 -
Food Research International (Ottawa,... Dec 2023Viruses are major pathogens that cause food poisoning when ingested via contaminated food and water. Therefore, the development of foodborne virus detection technologies... (Review)
Review
Viruses are major pathogens that cause food poisoning when ingested via contaminated food and water. Therefore, the development of foodborne virus detection technologies that can be applied throughout the food distribution chain is essential for food safety. A common nucleic acid-based detection method is polymerase chain reaction (PCR), which has become the gold standard for monitoring food contamination by viruses due to its high sensitivity, and availability of commercial kits. However, PCR-based methods are labor intensive and time consuming, and are vulnerable to inhibitors that may be present in food samples. In addition, the methods are restricted with regard to site of analysis due to the requirement of expensive and large equipment for sophisticated temperature regulation and signal analysis procedures. To overcome these limitations, optical and electrical readout biosensors based on nucleic acid isothermal amplification technology and nanomaterials have emerged as alternatives for nucleic acid-based detection of foodborne viruses. Biosensors are promising portable detection tools owing to their easy integration into compact platforms and ability to be operated on-site. However, the complexity of food components necessitates the inclusion of tedious preprocessing steps, and the lack of stability studies on residual food components further restricts the practical application of biosensors as a universal detection method. Here, we summarize the latest advances in nucleic acid-based strategies for the detection of foodborne viruses, including PCR-based and isothermal amplification-based methods, gene amplification-free methods, as well as food pretreatment methods. The principles, strengths/disadvantages, and performance of each method, problems to be solved, and future prospects for the development of a universal detection method are discussed.
Topics: Nucleic Acid Amplification Techniques; Polymerase Chain Reaction; Food Safety; Viruses; Nucleic Acids
PubMed: 37986417
DOI: 10.1016/j.foodres.2023.113502 -
Journal of Clinical Microbiology Dec 2023The emergence of [species HEV ( HEV)] as a causative agent of hepatitis E in humans presents a new potential threat to global public health. The genotype 1 (-1 HEV)...
The emergence of [species HEV ( HEV)] as a causative agent of hepatitis E in humans presents a new potential threat to global public health. The genotype 1 (-1 HEV) variant only shares 50%-60% genomic identity with [species HEV ( HEV)] variants, which are the main causes of hepatitis E infection in humans. Here, we report antigen diagnoses for -1 HEV and HEV using an enzymatic immunoassay (EIA) method. We detected recombinant virus-like particles protein (HEV 239) of HEV and HEV using a collection of hepatitis E virus (HEV)-specific monoclonal antibodies. Two optimal candidates, the capture antibody P#1-H4 and the detection antibodies C145 (P#1-H4*/C145) and C158 (P#1-H4*/C158), were selected to detect antigen in infected rat samples and -1 HEV- or HEV-infected human clinical samples. The two candidates showed similar diagnostic efficacy to the Wantai HEV antigen kit in HEV-infected clinical samples. Genomic divergence resulted in low diagnostic efficacy of the Wantai HEV antigen kit (0%, 0 of 10) for detecting -1 HEV infection. Compared with the P#1-H4*/C145 candidate (80%, 8 of 10), the P#1-H4*/C158 candidate had excellent diagnostic efficacy in -1 HEV-infected clinical samples (100%, 10 of 10). The two candidates bind to a discrete antigenic site that is highly conserved across HEV and HEV. P#1-H4*/C145 and P#1-H4*/C158 are efficacious candidate antibody combinations for rat HEV antigen detection.
Topics: Rats; Humans; Animals; Hepatitis E virus; Hepatitis E; Hepatitis Antibodies; Immunoenzyme Techniques; Immunologic Tests
PubMed: 38038482
DOI: 10.1128/jcm.00710-23 -
MBio Feb 2024Bacteriophages are large and diverse components of the biosphere, and many phages are temperate. Upon infection, temperate phages can establish lysogeny in which a...
Bacteriophages are large and diverse components of the biosphere, and many phages are temperate. Upon infection, temperate phages can establish lysogeny in which a prophage is typically integrated into the bacterial chromosome. Here, we describe the phenomenon of tRNA-dependent lysogeny, a previously unrecognized behavior of some temperate phages. tRNA-dependent lysogeny is characterized by two unusual features. First, a phage-encoded tyrosine family integrase mediates site-specific recombination between a phage site and a bacterial site overlapping a host tRNA gene. However, and share only a short (~10 bp) common core such that a functional tRNA is not reconstructed upon integration. Second, the phage encodes a tRNA of the same isotype as the disrupted but essential host tRNA, complementing its loss, and consequently is required for the survival of lysogenic progeny. As expected, an integrase-defective phage mutant forms turbid plaques, and bacterial progeny are immune to superinfection, but they lack stability, and the prophage is rapidly lost. In contrast, a tRNA-defective phage mutant forms clear plaques and more closely resembles a repressor mutant, and lysogens are recovered only at very low frequency through the use of secondary attachment sites elsewhere in the host genome. Integration-proficient plasmids derived from these phages must also carry a cognate phage tRNA gene for efficient integration, and these may be useful tools for mycobacterial genetics. We show that tRNA-dependent lysogeny is used by phages within multiple different groups of related viruses and may be prevalent elsewhere in the broader phage community.IMPORTANCEBacteriophages are the most numerous biological entities in the biosphere, and a substantial proportion of phages are temperate, forming stable lysogens in which a prophage copy of the genome integrates into the bacterial chromosome. Many phages encode a variety of tRNA genes whose roles are poorly understood, although it has been proposed that they enhance translational efficiencies in lytic growth or that they counteract host defenses that degrade host tRNAs. Here, we show that phage-encoded tRNAs play key roles in the establishment of lysogeny of some temperate phages. They do so by compensating for the loss of tRNA function when phages integrate at an site overlapping a tRNA gene but fail to reconstruct the tRNA at the attachment junction. In this system of tRNA-dependent lysogeny, the phage-encoded tRNA is required for lysogeny, and deletion of the phage tRNA gives rise to a clear plaque phenotype and obligate lytic growth.
Topics: Lysogeny; Bacteriophages; Prophages; Integrases; Plasmids
PubMed: 38236026
DOI: 10.1128/mbio.03260-23 -
Liver Cancer Feb 2024A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a...
INTRODUCTION
A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform.
METHODS
A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC.
RESULTS
They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort.
CONCLUSION
A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.
PubMed: 38344447
DOI: 10.1159/000530699