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Journal For Immunotherapy of Cancer Mar 2024The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs....
BACKGROUND
The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies.
METHODS
We constructed a recombinant oncolytic vaccinia virus encoding the hyaluronidase, and investigated its function in remodeling the ECM of the TME, the antitumor efficacy both in vitro and in several murine solid tumors either alone, or in combination with chemo drugs including doxorubicin and gemcitabine, with polypeptide liraglutide, with immune therapeutics such as PD-L1/PD-1 blockade, CD47 antibody, and with CAR-T cells.
RESULTS
Compared with control OVV, intratumoral injection of OVV-Hyal1 showed superior antitumor efficacies in a series of mouse subcutaneous tumor models. Moreover, HA degradation by OVV-Hyal1 resulted in increased intratumoral dissemination of chemo drugs, infiltration of T cells, NK cells, macrophages, and activation of CD8 T cells. When OVV-Hyal1 was combined with some antitumor therapeutics, for example, doxorubicin, gemcitabine, liraglutide, anti-PD-1, anti-CD47 blockade, or CAR-T cells, more profound therapeutic outcomes were obtained.
CONCLUSIONS
OVV-Hyal1 effectively degrades HA to reshape the TME, therefore overcoming some major hurdles in current cancer therapy, such as limited OVs spread, unfavored dissemination of chemo drugs, polypeptides, antibodies, and insufficient infiltration of effector immune cells. OVV-Hyal1 holds the promise to improve the antitumor outcomes of current cancer therapeutics.
Topics: Mice; Animals; Oncolytic Viruses; Vaccinia virus; Hyaluronoglucosaminidase; Oncolytic Virotherapy; Gemcitabine; CD8-Positive T-Lymphocytes; Liraglutide; Neoplasms; Immunotherapy; Disease Models, Animal; Peptides; Extracellular Matrix; Doxorubicin; Tumor Microenvironment
PubMed: 38458640
DOI: 10.1136/jitc-2023-008431 -
Cell Reports Mar 2024Numerous viruses alter host microtubule (MT) networks during infection, but how and why they induce these changes is unclear in many cases. We show that the vaccinia...
Numerous viruses alter host microtubule (MT) networks during infection, but how and why they induce these changes is unclear in many cases. We show that the vaccinia virus (VV)-encoded A51R protein is a MT-associated protein (MAP) that directly binds MTs and stabilizes them by both promoting their growth and preventing their depolymerization. Furthermore, we demonstrate that A51R-MT interactions are conserved across A51R proteins from multiple poxvirus genera, and highly conserved, positively charged residues in A51R proteins mediate these interactions. Strikingly, we find that viruses encoding MT interaction-deficient A51R proteins fail to suppress a reactive oxygen species (ROS)-dependent antiviral response in macrophages that leads to a block in virion morphogenesis. Moreover, A51R-MT interactions are required for VV virulence in mice. Collectively, our data show that poxviral MAP-MT interactions overcome a cell-intrinsic antiviral ROS response in macrophages that would otherwise block virus morphogenesis and replication in animals.
Topics: Animals; Mice; Reactive Oxygen Species; Virus Replication; Poxviridae; Vaccinia virus; Viral Proteins; Microtubules; Antiviral Agents
PubMed: 38457341
DOI: 10.1016/j.celrep.2024.113882 -
Narra J Apr 2023The recent spread of the monkeypox virus (MPXV), causing monkeypox (mpox), to non-endemic areas, and the atypical and unusual clinical manifestations observed during its... (Review)
Review
The recent spread of the monkeypox virus (MPXV), causing monkeypox (mpox), to non-endemic areas, and the atypical and unusual clinical manifestations observed during its 2022 outbreak has focused international interest on the clinical features of the disease. Mpox is usually a self-limiting disease with mild symptoms with common manifestations, including fever and skin lesions; however, severe manifestations could occur in some vulnerable groups (children and those with impaired immune systems) and may present multisystem complications and fatal outcomes. In most cases, a fever is the first sign of disease, followed by the development of various inflammatory lesions on the skin, such as vesiculopustular rashes and ulcers. Pneumonitis, encephalitis, keratitis, secondary bacterial infections, acute kidney injury, and myocarditis are all possible outcomes of the infection. Myocarditis has been reported to be caused by orthopoxviruses, and it is a serious condition of which its pathophysiology is little understood. Recent reports have indicated myocarditis with cardiac involvement as a possible atypical and unusual consequence of the MPXV infection during present outbreak. This review provides an overview of the clinical manifestations of mpox with a special focus on its effects on the heart, including myocarditis. The evidence of the myocarditis in mpox patients and its possible pathogenesis are discussed.
PubMed: 38450040
DOI: 10.52225/narra.v3i1.104 -
BMC Infectious Diseases Mar 2024Monkeypox virus (MPXV) is the causative agent of monkeypox's zoonotic infection and was declared a global emergency by the World Health Organization (WHO). Studies from...
BACKGROUND AND OBJECTIVE
Monkeypox virus (MPXV) is the causative agent of monkeypox's zoonotic infection and was declared a global emergency by the World Health Organization (WHO). Studies from different countries have shown insufficient knowledge among the general public on MPXV. This study aimed to assess the knowledge of the general public of Nepal on MPXV.
METHODS
Three hundred people were interviewed in person in October 2022, and 282 complete responses were recorded. The questionnaire related to the knowledge of MPXV was derived from a previous study conducted among the general population of Saudi Arabia. Twenty-two questions were included that assessed the knowledge and attitude of Nepalese toward monkeypox. Statistical comparison between high and low knowledge was performed using Pearson's Chi-square test. Logistic regression models were deployed to establish the relationship between participants' knowledge and socio-demographic characteristics.
RESULTS
Among the total respondents, 53.8% demonstrated high knowledge of monkeypox. People aged 18-25 years, unmarried people, and those living in urban areas had significantly higher levels of knowledge. Most respondents believed that MPXV is not a conspiracy or bioterrorism (63.1%) and agreed that it is likely to affect people's social and economic life as COVID-19 did (67.0%). The history of COVID-19 vaccination (aOR: 2.980; 95%CI: 1.227, 7.236) and the younger age (aOR: 2.975; 95%CI: 1.097, 8.069) were found to be significant determinants of the knowledge of the participants on monkeypox.
CONCLUSION
We observed that most Nepalese populations had a high knowledge of monkeypox and that social media was the most valuable source of information.
Topics: Humans; Adolescent; Young Adult; Adult; Monkeypox virus; Mpox (monkeypox); Cross-Sectional Studies; Nepal; Tertiary Care Centers; COVID-19 Vaccines; COVID-19; Demography
PubMed: 38448821
DOI: 10.1186/s12879-024-09184-5 -
Journal of Nanobiotechnology Mar 2024The human monkeypox virus (Mpox) is classified as a member of the Poxviridae family and belongs to the Orthopoxvirus genus. Mpox possesses double-stranded DNA, and there... (Review)
Review
The human monkeypox virus (Mpox) is classified as a member of the Poxviridae family and belongs to the Orthopoxvirus genus. Mpox possesses double-stranded DNA, and there are two known genetic clades: those originating in West Africa and the Congo Basin, commonly known as Central African clades. Mpox may be treated with either the vaccinia vaccination or the therapeutics. Modifying the smallpox vaccine for treating and preventing Mpox has shown to be beneficial because of the strong link between smallpox and Mpox viruses and their categorization in the same family. Cross-protection against Mpox is effective with two Food and Drug Administration (FDA)-approved smallpox vaccines (ACAM2000 and JYNNEOSTM). However, ACAM2000 has the potential for significant adverse effects, such as cardiac issues, whereas JYNNEOS has a lower risk profile. Moreover, Mpox has managed to resurface, although with modified characteristics, due to the discontinuation and cessation of the smallpox vaccine for 40 years. The safety and efficacy of the two leading mRNA vaccines against SARS-CoV-2 and its many variants have been shown in clinical trials and subsequent data analysis. This first mRNA treatment model involves injecting patients with messenger RNA to produce target proteins and elicit an immunological response. High potency, the possibility of safe administration, low-cost manufacture, and quick development is just a few of the benefits of RNA-based vaccines that pave the way for a viable alternative to conventional vaccines. When protecting against Mpox infection, mRNA vaccines are pretty efficient and may one day replace the present whole-virus vaccines. Therefore, the purpose of this article is to provide a synopsis of the ongoing research, development, and testing of an mRNA vaccine against Mpox.
Topics: United States; Humans; mRNA Vaccines; Smallpox Vaccine; Smallpox; COVID-19 Vaccines; Mpox (monkeypox); Antigens, Viral
PubMed: 38429829
DOI: 10.1186/s12951-024-02355-1 -
Cell Mar 2024The World Health Organization declared mpox a public health emergency of international concern in July 2022. To investigate global mpox transmission and population-level...
The World Health Organization declared mpox a public health emergency of international concern in July 2022. To investigate global mpox transmission and population-level changes associated with controlling spread, we built phylogeographic and phylodynamic models to analyze MPXV genomes from five global regions together with air traffic and epidemiological data. Our models reveal community transmission prior to detection, changes in case reporting throughout the epidemic, and a large degree of transmission heterogeneity. We find that viral introductions played a limited role in prolonging spread after initial dissemination, suggesting that travel bans would have had only a minor impact. We find that mpox transmission in North America began declining before more than 10% of high-risk individuals in the USA had vaccine-induced immunity. Our findings highlight the importance of broader routine specimen screening surveillance for emerging infectious diseases and of joint integration of genomic and epidemiological information for early outbreak control.
Topics: Humans; Communicable Diseases, Emerging; Disease Outbreaks; Epidemics; Mpox (monkeypox); Public Health; Monkeypox virus
PubMed: 38428425
DOI: 10.1016/j.cell.2024.02.003 -
Revista Colombiana de Obstetricia Y... Dec 2023
Topics: Female; Humans; Monkeypox virus; Mpox (monkeypox); Sexual Health; Women's Health
PubMed: 38421223
DOI: 10.18597/rcog.4149 -
Journal of Virology Mar 2024The role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 Spike (S) on disease pathogenesis was investigated. For this, we generated...
UNLABELLED
The role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 Spike (S) on disease pathogenesis was investigated. For this, we generated recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 S gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 strain genome. The recombinant viruses were characterized and . Viral entry, cell-cell fusion, plaque size, and the replication kinetics of the rWA1-Omi-S virus were markedly impaired when compared to the rWA1-D614G virus, demonstrating a lower fusogenicity and ability to spread cell-to-cell of rWA1-Omi-S. To assess the contribution of the Omicron BA.1 S protein to SARS-CoV-2 pathogenesis, the pathogenicity of rWA1-D614G and rWA1-Omi-S viruses was compared in a feline model. While the rWA1-D614G-inoculated cats were lethargic and showed increased body temperatures on days 2 and 3 post-infection (pi), rWA1-Omi-S-inoculated cats remained subclinical and gained weight throughout the 14-day experimental period. Animals inoculated with rWA1-D614G presented higher infectious virus shedding in nasal secretions, when compared to rWA1-Omi-S-inoculated animals. In addition, tissue replication of the rWA1-Omi-S was markedly reduced compared to the rWA1-D614G, as evidenced by lower viral load in tissues on days 3 and 5 pi. Histologic examination of the nasal turbinate and lungs revealed intense inflammatory infiltration in rWA1-D614G-inoculated animals, whereas rWA1-Omi-S-inoculated cats presented only mild to modest inflammation. Together, these results demonstrate that the S protein is a major virulence determinant for SARS-CoV-2 playing a major role for the attenuated phenotype of the Omicron virus.
IMPORTANCE
We have demonstrated that the Omicron BA.1.1 variant presents lower pathogenicity when compared to D614G (B.1) lineage in a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are over 50 mutations across the Omicron genome, of which more than two-thirds are present in the Spike (S) protein. To assess the role of the Omicron BA.1 S on virus pathogenesis, recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 Spike gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 were generated. While the Omicron BA.1 S promoted early entry into cells, it led to impaired fusogenic activity and cell-cell spread. Infection studies with the recombinant viruses in a relevant naturally susceptible feline model of SARS-CoV-2 infection here revealed an attenuated phenotype of rWA1-Omi-S, demonstrating that the Omi-S is a major determinant of the attenuated disease phenotype of Omicron strains.
Topics: Animals; Cats; COVID-19; Orthopoxvirus; Phenotype; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virulence; Virulence Factors
PubMed: 38421180
DOI: 10.1128/jvi.01902-23 -
Cureus Jan 2024Mpox is a viral zoonotic disease that is endemic in Central and West Africa and belongs to the genus. A global outbreak of mpox began in May 2022, mainly due to the...
Mpox is a viral zoonotic disease that is endemic in Central and West Africa and belongs to the genus. A global outbreak of mpox began in May 2022, mainly due to the transmission of the clade 11b virus through person-to-person contact with the lesions or scabs of a person infected with mpox. The data on mpox infection in the Caribbean is sparse. Here we report the clinical features and follow-up of the first two confirmed cases of mpox in Trinidad and Tobago (T&T). Both patients were men who have sex with men (MSM) who presented with genital lesions and expressed concern about increased stigma towards their already marginalized community.
PubMed: 38420056
DOI: 10.7759/cureus.53149 -
Oncoimmunology 2024Pancreatic ductal adenocarcinoma (PDAC) is currently difficult to treat, even when therapies are combined with immune checkpoint blockade (ICB). A novel strategy for...
Pancreatic ductal adenocarcinoma (PDAC) is currently difficult to treat, even when therapies are combined with immune checkpoint blockade (ICB). A novel strategy for immunotherapy would be to maximize the therapeutic potential of oncolytic viruses (OVs), which have been proven to engage the regulation of tumor microenvironment (TME) and cause-specific T-cell responses. To boost tumor sensitivity to ICB therapy, this study aimed to investigate how glutathione peroxide 4 (GPX4)-loaded OVs affect CD8 T cells and repair the immunosuppressive environment. Here, we successfully constructed a novel recombinant oncolytic vaccinia virus (OVV) encoding the mouse GPX4 gene. We found the OVV-GPX4 effectively replicated in tumor cells and prompted the expression of GPX4 in T cells. Our research indicated that OVV-GPX4 could reshape the TME, rectify the depletion of CD8T cells, and enhance the antitumor effects of ICB therapy.
Topics: Animals; Mice; Carcinoma, Pancreatic Ductal; CD8-Positive T-Lymphocytes; Oncolytic Virotherapy; Oncolytic Viruses; Pancreatic Neoplasms; Tumor Microenvironment; Vaccinia virus
PubMed: 38419758
DOI: 10.1080/2162402X.2024.2322173