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ELife Oct 2023Enterovirus D68 (EV-D68) is a re-emerging enterovirus that causes acute respiratory illness in infants and has recently been linked to Acute Flaccid Myelitis. Here, we...
Enterovirus D68 (EV-D68) is a re-emerging enterovirus that causes acute respiratory illness in infants and has recently been linked to Acute Flaccid Myelitis. Here, we show that the histone deacetylase, SIRT-1, is essential for autophagy and EV-D68 infection. Knockdown of SIRT-1 inhibits autophagy and reduces EV-D68 extracellular titers. The proviral activity of SIRT-1 does not require its deacetylase activity or functional autophagy. SIRT-1's proviral activity is, we demonstrate, mediated through the repression of endoplasmic reticulum stress (ER stress). Inducing ER stress through thapsigargin treatment or SERCA2A knockdown in SIRT-1 knockdown cells had no additional effect on EV-D68 extracellular titers. Knockdown of SIRT-1 also decreases poliovirus and SARS-CoV-2 titers but not coxsackievirus B3. In non-lytic conditions, EV-D68 is primarily released in an enveloped form, and SIRT-1 is required for this process. Our data show that SIRT-1, through its translocation to the cytosol, is critical to promote the release of enveloped EV-D68 viral particles.
Topics: Humans; COVID-19; Enterovirus; Enterovirus D, Human; Enterovirus Infections; Neuromuscular Diseases; Proviruses; SARS-CoV-2; Viral Envelope; Virus Activation; Sirtuin 1
PubMed: 37850626
DOI: 10.7554/eLife.87993 -
International Journal of Molecular... Aug 2023CD155, also known as the poliovirus receptor, is an adhesion molecule often overexpressed in tumors of different origins where it promotes cell migration and... (Review)
Review
CD155, also known as the poliovirus receptor, is an adhesion molecule often overexpressed in tumors of different origins where it promotes cell migration and proliferation. In addition to this pro-tumorigenic function, CD155 plays an immunomodulatory role during tumor progression since it is a ligand for both the activating receptor DNAM-1 and the inhibitory receptor TIGIT, expressed on cytotoxic innate and adaptative lymphocytes. DNAM-1 is a well-recognized receptor involved in anti-tumor immune surveillance. However, in advanced tumor stages, TIGIT is up-regulated and acts as an immune checkpoint receptor, counterbalancing DNAM-1-mediated cancer cell clearance. Pre-clinical studies have proposed the direct targeting of CD155 on tumor cells as well as the enhancement of DNAM-1-mediated anti-tumor functions as promising therapeutic approaches. Moreover, immunotherapeutic use of anti-TIGIT blocking antibody alone or in combined therapy has already been included in clinical trials. The aim of this review is to summarize all these potential therapies, highlighting the still controversial role of CD155 during tumor progression.
Topics: Humans; Carcinogenesis; Cell Movement; Receptors, Virus; Receptors, Immunologic; Antigens, Differentiation, T-Lymphocyte; Animals
PubMed: 37629138
DOI: 10.3390/ijms241612958 -
Nature Communications Oct 2023Wastewater is a discarded human by-product, but its analysis may help us understand the health of populations. Epidemiologists first analyzed wastewater to track...
Wastewater is a discarded human by-product, but its analysis may help us understand the health of populations. Epidemiologists first analyzed wastewater to track outbreaks of poliovirus decades ago, but so-called wastewater-based epidemiology was reinvigorated to monitor SARS-CoV-2 levels while bypassing the difficulties and pit falls of individual testing. Current approaches overlook the activity of most human viruses and preclude a deeper understanding of human virome community dynamics. Here, we conduct a comprehensive sequencing-based analysis of 363 longitudinal wastewater samples from ten distinct sites in two major cities. Critical to detection is the use of a viral probe capture set targeting thousands of viral species or variants. Over 450 distinct pathogenic viruses from 28 viral families are observed, most of which have never been detected in such samples. Sequencing reads of established pathogens and emerging viruses correlate to clinical data sets of SARS-CoV-2, influenza virus, and monkeypox viruses, outlining the public health utility of this approach. Viral communities are tightly organized by space and time. Finally, the most abundant human viruses yield sequence variant information consistent with regional spread and evolution. We reveal the viral landscape of human wastewater and its potential to improve our understanding of outbreaks, transmission, and its effects on overall population health.
Topics: Humans; Virome; Wastewater; Cities; Disease Outbreaks; Poliovirus; SARS-CoV-2
PubMed: 37898601
DOI: 10.1038/s41467-023-42064-1 -
Nature Jul 2023Vaccination with Sabin, a live attenuated oral polio vaccine (OPV), results in robust intestinal and humoral immunity and has been key to controlling poliomyelitis. As...
Vaccination with Sabin, a live attenuated oral polio vaccine (OPV), results in robust intestinal and humoral immunity and has been key to controlling poliomyelitis. As with any RNA virus, OPV evolves rapidly to lose attenuating determinants critical to the reacquisition of virulence resulting in vaccine-derived, virulent poliovirus variants. Circulation of these variants within underimmunized populations leads to further evolution of circulating, vaccine-derived poliovirus with higher transmission capacity, representing a significant risk of polio re-emergence. A new type 2 OPV (nOPV2), with promising clinical data on genetic stability and immunogenicity, recently received authorization from the World Health Organization for use in response to circulating, vaccine-derived poliovirus outbreaks. Here we report the development of two additional live attenuated vaccine candidates against type 1 and 3 polioviruses. The candidates were generated by replacing the capsid coding region of nOPV2 with that from Sabin 1 or 3. These chimeric viruses show growth phenotypes similar to nOPV2 and immunogenicity comparable to their parental Sabin strains, but are more attenuated. Our experiments in mice and deep sequencing analysis confirmed that the candidates remain attenuated and preserve all the documented nOPV2 characteristics concerning genetic stability following accelerated virus evolution. Importantly, these vaccine candidates are highly immunogenic in mice as monovalent and multivalent formulations and may contribute to poliovirus eradication.
Topics: Animals; Mice; Disease Models, Animal; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Vaccines, Attenuated; Disease Eradication
PubMed: 37316671
DOI: 10.1038/s41586-023-06212-3 -
Human Vaccines & Immunotherapeutics Aug 2023Conflict poses a threat to the stability of health-care systems around the world. Within the context of immunization service delivery, conflict-affected geographies are... (Review)
Review
Conflict poses a threat to the stability of health-care systems around the world. Within the context of immunization service delivery, conflict-affected geographies are often dogged by recurrent disease outbreaks due to the inability to administer life-saving vaccines to children residing in these areas. Essential immunization coverage is often poor in conflict-affected geographies, and within the specific context of the Global Polio Eradication Initiative (GPEI), multiple rounds of supplementary immunization activities are often needed to compensate for the inability to provide adequate immunization services. In order to implement polio vaccination activities, GPEI has often resorted to innovative approaches to reach and vaccinate children in security-compromised areas. This article examines the approaches adopted by the global polio program in conducting vaccination activities in conflict-affected geographies with the aim of understanding how they have influenced the successes and setbacks of the program in its bid to eradicate all polioviruses.
Topics: Child; Humans; Animals; Dogs; Vaccination; Immunization; Behavior Therapy; Vaccination Coverage; Poliomyelitis
PubMed: 37489591
DOI: 10.1080/21645515.2023.2237390 -
Journal of the National Cancer Institute Mar 2024Poliovirus receptor interacts with 3 receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif, CD96, and DNAX accessory molecule 1, which are...
BACKGROUND
Poliovirus receptor interacts with 3 receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif, CD96, and DNAX accessory molecule 1, which are predominantly expressed on T cells and natural killer (NK) cells. Many solid tumors, including IDH wild-type glioblastoma, have been reported to overexpress poliovirus receptor, and this overexpression is associated with poor prognosis. However, there are no preclinical or clinical trials investigating the use of cell-based immunotherapies targeting poliovirus receptor in IDH wild-type glioblastoma.
METHODS
We analyzed poliovirus receptor expression in transcriptome sequencing databases and specimens from IDH wild-type glioblastoma patients. We developed poliovirus receptor targeting chimeric antigen receptor T cells using lentivirus. The antitumor activity of chimeric antigen receptor T cells was demonstrated in patient-derived glioma stem cells, intracranial and subcutaneous mouse xenograft models.
RESULTS
We verified poliovirus receptor expression in primary glioma stem cells, surgical specimens from IDH wild-type glioblastoma patients, and organoids. Accordingly, we developed poliovirus receptor-based second-generation chimeric antigen receptor T cells. The antitumor activity of chimeric antigen receptor T cells was demonstrated in glioma stem cells and xenograft models. Tumor recurrence occurred in intracranial xenograft models because of antigen loss. The combinational therapy of tyrosine-based inhibitory motif extracellular domain-based chimeric antigen receptor T cells and NK-92 cells markedly suppressed tumor recurrence and prolonged survival.
CONCLUSIONS
Poliovirus receptor-based chimeric antigen receptor T cells were capable of killing glioma stem cells and suppressing tumor recurrence when combined with NK-92 cells.
Topics: Humans; Animals; Mice; Glioblastoma; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Killer Cells, Natural; T-Lymphocytes; Tyrosine; Cell Line, Tumor; Receptors, Virus
PubMed: 37944044
DOI: 10.1093/jnci/djad226 -
Nature Microbiology Sep 2023Timely detection of outbreaks is needed for poliovirus eradication, but gold standard detection in the Democratic Republic of the Congo takes 30 days (median). Direct...
Timely detection of outbreaks is needed for poliovirus eradication, but gold standard detection in the Democratic Republic of the Congo takes 30 days (median). Direct molecular detection and nanopore sequencing (DDNS) of poliovirus in stool samples is a promising fast method. Here we report prospective testing of stool samples from suspected polio cases, and their contacts, in the Democratic Republic of the Congo between 10 August 2021 and 4 February 2022. DDNS detected polioviruses in 62/2,339 (2.7%) of samples, while gold standard combination of cell culture, quantitative PCR and Sanger sequencing detected polioviruses in 51/2,339 (2.2%) of the same samples. DDNS provided case confirmation in 7 days (median) in routine surveillance conditions. DDNS enabled confirmation of three serotype 2 circulating vaccine-derived poliovirus outbreaks 23 days (mean) earlier (range 6-30 days) than the gold standard method. The mean sequence similarity between sequences obtained by the two methods was 99.98%. Our data confirm the feasibility of implementing DDNS in a national poliovirus laboratory.
Topics: Poliovirus; Nanopore Sequencing; Polymerase Chain Reaction; Dansyl Compounds
PubMed: 37591995
DOI: 10.1038/s41564-023-01453-4 -
Nature Communications Oct 2023Global eradication of poliovirus remains elusive, and it is critical to develop next generation vaccines and antivirals. In support of this goal, we map the epitope of...
Global eradication of poliovirus remains elusive, and it is critical to develop next generation vaccines and antivirals. In support of this goal, we map the epitope of human monoclonal antibody 9H2 which is able to neutralize the three serotypes of poliovirus. Using cryo-EM we solve the near-atomic structures of 9H2 fragments (Fab) bound to capsids of poliovirus serotypes 1, 2, and 3. The Fab-virus complexes show that Fab interacts with the same binding mode for each serotype and at the same angle of interaction relative to the capsid surface. For each of the Fab-virus complexes, we find that the binding site overlaps with the poliovirus receptor (PVR) binding site and maps across and into a depression in the capsid called the canyon. No conformational changes to the capsid are induced by Fab binding for any complex. Competition binding experiments between 9H2 and PVR reveal that 9H2 impedes receptor binding. Thus, 9H2 outcompetes the receptor to neutralize poliovirus. The ability to neutralize all three serotypes, coupled with the critical importance of the conserved receptor binding site make 9H2 an attractive antiviral candidate for future development.
Topics: Humans; Serogroup; Antibodies, Monoclonal; Capsid Proteins; Poliovirus; Binding Sites; Antibodies, Viral
PubMed: 37816742
DOI: 10.1038/s41467-023-41052-9 -
MMWR. Morbidity and Mortality Weekly... Jul 2023This report describes the status of introductions globally for eight World Health Organization (WHO)-recommended new and underutilized vaccines, comprising 10 individual...
This report describes the status of introductions globally for eight World Health Organization (WHO)-recommended new and underutilized vaccines, comprising 10 individual vaccine antigens. By 2021, among 194 countries worldwide, 33 (17%) provided all of these 10 WHO-recommended antigens as part of their routine immunization schedules; only one low-income country had introduced all of these recommended vaccines. Universal hepatitis B birth dose; human papillomavirus vaccine; rotavirus vaccine; and diphtheria, tetanus, and pertussis-containing vaccine first booster dose have been introduced by 57%, 59%, 60%, and 72% of all countries worldwide, respectively. Pneumococcal conjugate vaccine, rubella-containing vaccine, measles-containing vaccine second dose, and Haemophilus influenzae type b vaccine have been introduced by 78%, 89%, 94%, and 99% of all countries, respectively. The annual rate of new vaccine introductions declined precipitously when the COVID-19 pandemic started, from 48 in 2019 to 15 in 2020 before rising to 26 in 2021. Increased efforts to accelerate new and underutilized vaccine introductions are urgently needed to improve universal equitable access to all recommended vaccines to achieve the global Immunization Agenda 2021-2030 (IA2030) targets.
Topics: Humans; Infant; Diphtheria-Tetanus-Pertussis Vaccine; Pandemics; Haemophilus Vaccines; COVID-19; Vaccination; Measles Vaccine; Rubella Vaccine; Immunization Schedule; Poliovirus Vaccine, Inactivated; Hepatitis B Vaccines; Vaccines, Combined
PubMed: 37410663
DOI: 10.15585/mmwr.mm7227a2 -
Proceedings of the National Academy of... Aug 2023RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions...
RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions (indels) in viral genomes are major contributors to both deleterious mutational load and evolutionary novelty, but remain understudied. To characterize the mechanistic details of their formation and evolutionary dynamics during infection, we developed a hybrid experimental-bioinformatic approach. This approach, called MultiMatch, extracts insertions and deletions from ultradeep sequencing experiments, including those occurring at extremely low frequencies, allowing us to map their genomic distribution and quantify the rates at which they occur. Mapping indel mutations in adapting poliovirus and dengue virus populations, we determine the rates of indel generation and identify mechanistic and functional constraints shaping indel diversity. Using poliovirus RdRp variants of distinct fidelity and genome recombination rates, we demonstrate tradeoffs between fidelity and Indel generation. Additionally, we show that maintaining translation frame and viral RNA structures constrain the Indel landscape and that, due to these significant fitness effects, Indels exert a significant deleterious load on adapting viral populations. Conversely, we uncover positively selected Indels that modulate RNA structure, generate protein variants, and produce defective interfering genomes in viral populations. Together, our analyses establish the kinetic and mechanistic tradeoffs between misincorporation, recombination, and Indel rates and reveal functional principles defining the central role of Indels in virus evolution, emergence, and the regulation of viral infection.
Topics: Evolution, Molecular; Genome; Mutation Rate; INDEL Mutation; RNA, Viral; RNA Viruses
PubMed: 37487061
DOI: 10.1073/pnas.2304667120