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Frontiers in Immunology 2024Activated lung ILC2s produce large quantities of IL-5 and IL-13 that contribute to eosinophilic inflammation and mucus production following respiratory syncytial virus...
Activated lung ILC2s produce large quantities of IL-5 and IL-13 that contribute to eosinophilic inflammation and mucus production following respiratory syncytial virus infection (RSV). The current understanding of ILC2 activation during RSV infection, is that ILC2s are activated by alarmins, including IL-33, released from airway epithelial cells in response to viral-mediated damage. Thus, high levels of RSV neutralizing maternal antibody generated from maternal immunization would be expected to reduce IL-33 production and mitigate ILC2 activation. Here we report that lung ILC2s from mice born to RSV-immunized dams become activated despite undetectable RSV replication. We also report, for the first time, expression of activating and inhibitory Fcgamma receptors on ILC2s that are differentially expressed in offspring born to immunized versus unimmunized dams. Alternatively, ex vivo IL-33-mediated activation of ILC2s was mitigated following the addition of antibody: antigen immune complexes. Further studies are needed to confirm the role of Fcgamma receptor ligation by immune complexes as an alternative mechanism of ILC2 regulation in RSV-associated eosinophilic lung inflammation.
Topics: Animals; Respiratory Syncytial Virus Infections; Mice; Female; Mice, Inbred BALB C; Lung; Interleukin-33; Respiratory Syncytial Viruses; Lymphocytes; Immunization; Receptors, IgG; Antibodies, Viral; Pregnancy; Respiratory Syncytial Virus Vaccines
PubMed: 38827738
DOI: 10.3389/fimmu.2024.1374818 -
Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeutics.EBioMedicine Jun 2024Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola...
BACKGROUND
Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP) have shown promise in improving prognosis, their effectiveness in mitigating ocular sequelae remains uncertain.
METHODS
We developed and characterized a BSL-2-compatible immunocompetent mouse model to evaluate therapeutics targeting EBOV-GP by inoculating neonatal mice with vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV). To examine the impact of anti-EBOV-GP antibody treatment on acute retinitis and ocular sequelae, VSV-EBOV-infected mice were treated with polyclonal antibodies or monoclonal antibody preparations with antibody-dependent cellular cytotoxicity (ADCC-mAb) or neutralizing activity (NEUT-mAb).
FINDINGS
Treatment with all anti-EBOV-GP antibodies tested dramatically reduced viremia and improved survival. Further, all treatments reduced the incidence of cataracts. However, NEUT-mAb alone or in combination with ADCC-mAb reduced viral load in the eyes, downregulated the ocular immune and inflammatory responses, and minimized retinal damage more effectively.
INTERPRETATION
Anti-EBOV-GP antibodies can improve survival among EVD patients, but improved therapeutics are needed to reduce life altering sequelae. This animal model offers a new platform to examine the acute and long-term effect of the virus in the eye and the relative impact of therapeutic candidates targeting EBOV-GP. Results indicate that even antibodies that improve systemic viral clearance and survival can differ in their capacity to reduce acute ocular inflammation, and long-term retinal pathology and corneal degeneration.
FUNDING
This study was partly supported by Postgraduate Research Fellowship Awards from ORISE through an interagency agreement between the US DOE and the US FDA.
Topics: Animals; Mice; Disease Models, Animal; Ebolavirus; Hemorrhagic Fever, Ebola; Antibodies, Viral; Antibodies, Monoclonal; Humans; Viral Load; Glycoproteins; Viral Envelope Proteins; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity
PubMed: 38823088
DOI: 10.1016/j.ebiom.2024.105170 -
Scientific Reports May 2024Rabies virus (RABV) causes fatal neurological disease. Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) using inactivated-virus vaccines are the most...
Rabies virus (RABV) causes fatal neurological disease. Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) using inactivated-virus vaccines are the most effective measures to prevent rabies. In Japan, HEP-Flury, the viral strain, used as a human rabies vaccine, has historically been propagated in primary fibroblast cells derived from chicken embryos. In the present study, to reduce the cost and labor of vaccine production, we sought to adapt the original HEP-Flury (HEP) to Vero cells. HEP was repeatedly passaged in Vero cells to generate ten- (HEP-10V) and thirty-passaged (HEP-30V) strains. Both HEP-10V and HEP-30V grew significantly better than HEP in Vero cells, with virulence and antigenicity similar to HEP. Comparison of the complete genomes with HEP revealed three non-synonymous mutations in HEP-10V and four additional non-synonymous mutations in HEP-30V. Comparison among 18 recombinant HEP strains constructed by reverse genetics and vesicular stomatitis viruses pseudotyped with RABV glycoproteins indicated that the substitution P(L115H) in the phosphoprotein and G(S15R) in the glycoprotein improved viral propagation in HEP-10V, while in HEP-30V, G(V164E), G(L183P), and G(A286V) in the glycoprotein enhanced entry into Vero cells. The obtained recombinant RABV strain, rHEP-PG4 strain, with these five substitutions, is a strong candidate for production of human rabies vaccine.
Topics: Animals; Vero Cells; Chlorocebus aethiops; Rabies Vaccines; Rabies virus; Amino Acid Substitution; Humans; Rabies; Genome, Viral
PubMed: 38822013
DOI: 10.1038/s41598-024-63337-9 -
Nature Communications May 2024The Paramyxoviridae family encompasses medically significant RNA viruses, including human respiroviruses 1 and 3 (RV1, RV3), and zoonotic pathogens like Nipah virus...
The Paramyxoviridae family encompasses medically significant RNA viruses, including human respiroviruses 1 and 3 (RV1, RV3), and zoonotic pathogens like Nipah virus (NiV). RV3, previously known as parainfluenza type 3, for which no vaccines or antivirals have been approved, causes respiratory tract infections in vulnerable populations. The RV3 fusion (F) protein is inherently metastable and will likely require prefusion (preF) stabilization for vaccine effectiveness. Here we used structure-based design to stabilize regions involved in structural transformation to generate a preF protein vaccine antigen with high expression and stability, and which, by stabilizing the coiled-coil stem region, does not require a heterologous trimerization domain. The preF candidate induces strong neutralizing antibody responses in both female naïve and pre-exposed mice and provides protection in a cotton rat challenge model (female). Despite the evolutionary distance of paramyxovirus F proteins, their structural transformation and local regions of instability are conserved, which allows successful transfer of stabilizing substitutions to the distant preF proteins of RV1 and NiV. This work presents a successful vaccine antigen design for RV3 and provides a toolbox for future paramyxovirus vaccine design and pandemic preparedness.
Topics: Animals; Female; Viral Fusion Proteins; Mice; Sigmodontinae; Viral Vaccines; Antibodies, Neutralizing; Antibodies, Viral; Humans; Mice, Inbred BALB C; Paramyxoviridae Infections; Parainfluenza Virus 3, Human
PubMed: 38821950
DOI: 10.1038/s41467-024-48059-w -
Euro Surveillance : Bulletin Europeen... May 2024A measles outbreak with 51 cases occurred in the canton of Vaud, Switzerland, between January and March 2024. The outbreak was triggered by an imported case, and 37...
A measles outbreak with 51 cases occurred in the canton of Vaud, Switzerland, between January and March 2024. The outbreak was triggered by an imported case, and 37 (72.5%) subsequent cases were previously vaccinated individuals. Epidemiological investigations showed that vaccinated measles cases were symptomatic and infectious. In a highly vaccinated population, it is important to raise awareness among healthcare professionals to suspect and test for measles virus when an outbreak is declared, irrespective of the vaccination status of the patients.
Topics: Humans; Measles; Switzerland; Disease Outbreaks; Measles Vaccine; Vaccination; Male; Female; Adult; Adolescent; Child; Measles virus; Child, Preschool; Young Adult; Infant
PubMed: 38818746
DOI: 10.2807/1560-7917.ES.2024.29.22.2400275 -
BMC Infectious Diseases May 2024In 2022, an Ebola disease outbreak caused by Sudan virus (SUDV) occurred in Uganda, primarily affecting Mubende and Kassanda districts. We determined risk factors for...
BACKGROUND
In 2022, an Ebola disease outbreak caused by Sudan virus (SUDV) occurred in Uganda, primarily affecting Mubende and Kassanda districts. We determined risk factors for SUDV infection among household members (HHM) of cases.
METHODS
We conducted a case-control and retrospective cohort study in January 2023. Cases were RT-PCR-confirmed SUDV infection in residents of Mubende or Kassanda districts during the outbreak. Case-households housed a symptomatic, primary case-patient for ≥ 24 h and had ≥ 1 secondary case-patient with onset < 2 weeks after their last exposure to the primary case-patient. Control households housed a case-patient and other HHM but no secondary cases. A risk factor questionnaire was administered to the primary case-patient or another adult who lived at home while the primary case-patient was ill. We conducted a retrospective cohort study among case-household members and categorized their interactions with primary case-patients during their illnesses as none, minimal, indirect, and direct contact. We conducted logistic regression to explore associations between exposures and case-household status, and Poisson regression to identify risk factors for SUDV infection among HHM.
RESULTS
Case- and control-households had similar median sizes. Among 19 case-households and 51 control households, primary case-patient death (adjusted odds ratio [OR] = 7.6, 95% CI 1.4-41) and ≥ 2 household bedrooms (OR=0.19, 95% CI 0.056-0.71) were associated with case-household status. In the cohort of 76 case-HHM, 44 (58%) were tested for SUDV < 2 weeks from their last contact with the primary case-patient; 29 (38%) were positive. Being aged ≥ 18 years (adjusted risk ratio [aRR] = 1.9, 95%CI: 1.01-3.7) and having direct or indirect contact with the primary case-patient (aRR=3.2, 95%CI: 1.1-9.7) compared to minimal or no contact increased risk of Sudan virus disease (SVD). Access to a handwashing facility decreased risk (aRR=0.52, 95%CI: 0.31-0.88).
CONCLUSION
Direct contact, particularly providing nursing care for and sharing sleeping space with SVD patients, increased infection risk among HHM. Risk assessments during contact tracing may provide evidence to justify closer monitoring of some HHM. Health messaging should highlight the risk of sharing sleeping spaces and providing nursing care for persons with Ebola disease symptoms and emphasize hand hygiene to aid early case identification and reduce transmission.
Topics: Humans; Uganda; Hemorrhagic Fever, Ebola; Risk Factors; Male; Adult; Female; Retrospective Studies; Case-Control Studies; Family Characteristics; Adolescent; Young Adult; Disease Outbreaks; Middle Aged; Child; Child, Preschool; Ebolavirus; Infant
PubMed: 38816800
DOI: 10.1186/s12879-024-09439-1 -
Journal of Integrative Neuroscience Apr 2024The genome of the Nipah virus (NiV) encodes a variety of structural proteins linked to a diverse array of symptoms, including fevers, headaches, somnolence, and... (Review)
Review
The genome of the Nipah virus (NiV) encodes a variety of structural proteins linked to a diverse array of symptoms, including fevers, headaches, somnolence, and respiratory impairment. In instances of heightened severity, it can also invade the central nervous system (CNS), resulting in more pronounced problems. This work investigates the effects of NiV on the blood-brain barrier (BBB), the vital physiological layer responsible for safeguarding the CNS by regulating the passage of chemicals into the brain selectively. To achieve this, the researchers (MMJAO, AM and MNMD) searched a variety of databases for relevant articles on NiV and BBB disruption, looking for evidence of work on inflammation, immune response (cytokines and chemokines), tight junctions (TJs), and basement membranes related to NiV and BBB. Based on these works, it appears that the affinity of NiV for various receptors, including Ephrin-B2 and Ephrin-B3, has seen many NiV infections begin in the respiratory epithelium, resulting in the development of acute respiratory distress syndrome. The virus then gains entry into the circulatory system, offering it the potential to invade brain endothelial cells (ECs). NiV also has the ability to infect the leukocytes and the olfactory pathway, offering it a "Trojan horse" strategy. When NiV causes encephalitis, the CNS generates a strong inflammatory response, which makes the blood vessels more permeable. Chemokines and cytokines all have a substantial influence on BBB disruption, and NiV also has the ability to affect TJs, leading to disturbances in the structural integrity of the BBB. The pathogen's versatility is also shown by its capacity to impact multiple organ systems, despite particular emphasis on the CNS. It is of the utmost importance to comprehend the mechanisms by which NiV impacts the integrity of the BBB, as such comprehension has the potential to inform treatment approaches for NiV and other developing viral diseases. Nevertheless, the complicated pathophysiology and molecular pathways implicated in this phenomenon have offered several difficult challenges to researchers to date, underscoring the need for sustained scientific investigation and collaboration in the ongoing battle against this powerful virus.
Topics: Blood-Brain Barrier; Nipah Virus; Humans; Henipavirus Infections; Animals; Viral Tropism
PubMed: 38812392
DOI: 10.31083/j.jin2305090 -
Frontiers in Bioscience (Landmark... May 2024To investigate the immune responses and protection ability of ultraviolet light (UV)-inactivated recombinant vesicular stomatitis (rVSV)-based vectors that expressed a...
BACKGROUND
To investigate the immune responses and protection ability of ultraviolet light (UV)-inactivated recombinant vesicular stomatitis (rVSV)-based vectors that expressed a fusion protein consisting of four copies of the influenza matrix 2 protein ectodomain (tM2e) and the Dendritic Cell (DC)-targeting domain of the Ebola Glycoprotein (EΔM), (rVSV-EΔM-tM2e).
METHOD
In our previous study, we demonstrated the effectiveness of rVSV-EΔM-tM2e to induce robust immune responses against influenza M2e and protect against lethal challenges from H1N1 and H3N2 strains. Here, we used UV to inactivate rVSV-EΔM-tM2e and tested its immunogenicity and protection in BALB/c mice from a mouse-adapted H1N1 influenza challenge. Using Enzyme-Linked Immunosorbent Assay (ELISA) and Antibody-Dependent Cellular Cytotoxicity (ADCC), the influenza anti-M2e immune responses specific to human, avian and swine influenza strains induced were characterized. Likewise, the specificity of the anti-M2e immune responses induced in recognizing M2e antigen on the surface of the cell was investigated using Fluorescence-Activated Cell Sorting (FACS) analysis.
RESULTS
Like the live attenuated rVSV-EΔM-tM2e, the UV-inactivated rVSV-EΔM-tM2e was highly immunogenic against different influenza M2e from strains of different hosts, including human, swine, and avian, and protected against influenza H1N1 challenge in mice. The FACS analysis demonstrated that the induced immune responses can recognize influenza M2 antigens from human, swine and avian influenza strains. Moreover, the rVSV-EΔM-tM2e also induced ADCC activity against influenza M2e from different host strains.
CONCLUSIONS
These findings suggest that UV-inactivated rVSV-EΔM-tM2e could be used as an inactivated vaccine against influenza viruses.
Topics: Animals; Influenza Vaccines; Influenza A Virus, H1N1 Subtype; Ultraviolet Rays; Mice, Inbred BALB C; Orthomyxoviridae Infections; Female; Mice; Humans; Viral Matrix Proteins; Vesiculovirus; Vaccines, Inactivated
PubMed: 38812326
DOI: 10.31083/j.fbl2905195 -
Open Veterinary Journal Apr 2024Canine distemper (CD) is a worldwide spread disease that has been described in 12 families of mammals, especially in the Carnivora order, being better studied in...
BACKGROUND
Canine distemper (CD) is a worldwide spread disease that has been described in 12 families of mammals, especially in the Carnivora order, being better studied in domestic canines where vaccination represents the best means of control. CD is controlled by vaccination, but many cases of the disease still occur in vaccinated animals.
AIM
The aim of this work was to study antigen-specific epitopes that can subsidize the development of a new vaccine approach.
METHODS
Mapping of T cell reactive epitopes for CD virus (CDV) was carried out through enzyme-linked immunospot assays using 119 overlapped synthetic peptides from the viral hemagglutinin protein, grouped in 22 pools forming a matrix to test the immune response of 32 animals.
RESULTS
Evaluations using the criteria established to identify reactive pools, demonstrated that 26 animals presented at least one reactive pool, that one pool was not reactive to any animal, and six pools were the most frequent among the reactive peptides. The crisscrossing of the most reactive pools in the matrix revealed nine peptides considered potential candidate epitopes for T cell stimulation against the CDV and those were used to design an protein, containing also predicted epitopes for B cell stimulation, and further analyzed using immune epitope databases to ensure protein quality and stability.
CONCLUSION
The final optimized protein presents characteristics that qualify it to be used to develop a new prototype epitope-based anti-CDV vaccine.
Topics: Distemper Virus, Canine; Animals; Distemper; Epitope Mapping; Dogs; Viral Vaccines; Epitopes, T-Lymphocyte; Enzyme-Linked Immunospot Assay
PubMed: 38808294
DOI: 10.5455/OVJ.2024.v14.i4.9 -
Journal of Ethnopharmacology Oct 2024WuHuTang (WHT) is a traditional Chinese medicine compound for treating asthma, and the evidence supports that it has a good effect on acute asthma attacks in children...
ETHNOPHARMACOLOGICAL RELEVANCE
WuHuTang (WHT) is a traditional Chinese medicine compound for treating asthma, and the evidence supports that it has a good effect on acute asthma attacks in children and adults. Respiratory syncytial virus (RSV) is an important factor in the pathogenesis of acute asthma attacks, and the effect on dendritic cells is the key to its pathogenesis. Previous studies have confirmed that the pathogenesis of viruses is related to exosomes. However, there are few studies on the exosomes induced by RSV. Whether WHT can improve the changes caused by RSV-induced exosomes or not is worthy of further exploration.
AIM OF THE STUDY
We aim to study the effects of RSV-induced exosomes on the function and autophagy of dendritic cells, and to observe the intervention effect of WHT serum on the above effects.
METHODS
The co-culture model of exosomes derived from bone marrow mesenchymal stem cells induced by RSV (BMSCs-Exo-RSV) and dendritic cells was established, and then WHT serum was used to intervene. After 24 h of intervention, the CCK-8 method, flow cytometry, Elisa, RT-qCPR, and Western blot were used to detect the above-mentioned culture model.
RESULTS
RSV-induced exosomes had certain effects on viability, apoptosis, and costimulatory molecules generation of dendritic cells. At the same time, the levels of IL-6, IL-12, TNF-α, and autophagy increased, while the levels of IL-4, IL-10, and TGF-β decreased, and the AKT/TSC/mTOR pathway was inhibited. WHT serum could activate this pathway and reverse the above changes in dendritic cells.
CONCLUSION
This study reveals that the pathogenic effect of RSV is related to the exosomes induced by RSV. The exosomes induced by RSV affect the function of dendritic cells by inhibiting the AKT/TSC/mTOR pathway, which can be activated by WHT to reverse the effects caused by RSV-induced exosomes.
Topics: Dendritic Cells; Exosomes; Autophagy; Drugs, Chinese Herbal; Animals; TOR Serine-Threonine Kinases; Apoptosis; Coculture Techniques; Mesenchymal Stem Cells; Respiratory Syncytial Viruses; Cells, Cultured; Proto-Oncogene Proteins c-akt; Cytokines; Respiratory Syncytial Virus Infections; Cell Survival
PubMed: 38806137
DOI: 10.1016/j.jep.2024.118397