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Microbiology Spectrum Sep 2023Human telomerase RNA (hTR) is overexpressed in many cancers and protects T cells from apoptosis in a telomerase-independent manner. The most prevalent cancer in the...
Human telomerase RNA (hTR) is overexpressed in many cancers and protects T cells from apoptosis in a telomerase-independent manner. The most prevalent cancer in the animal kingdom is caused by the highly oncogenic herpesvirus Marek's disease virus (MDV). MDV encodes a viral telomerase RNA (vTR) that plays a crucial role in MDV-induced tumorigenesis and shares all four conserved functional domains with hTR. In this study, we assessed whether hTR drives tumor formation in this natural model of herpesvirus-induced tumorigenesis. Therefore, we replaced vTR with hTR in the genome of a highly oncogenic MDV. Furthermore, we investigated the anti-apoptotic activity of vTR, hTR, and their counterpart in the chicken [chicken telomerase RNA (cTR)]. hTR was efficiently expressed and did not alter replication of the recombinant virus. Despite its conserved structure, hTR did not complement the loss of vTR in virus-induced tumorigenesis. Strikingly, hTR did not inhibit apoptosis in chicken cells, but efficiently inhibited apoptosis in human cells. Inverse host restriction has been observed for vTR and cTR in human cells. Our data revealed that vTR, cTR, and hTR possess conserved but host-specific anti-apoptotic functions that likely contribute to MDV-induced tumorigenesis. IMPORTANCE hTR is overexpressed in many cancers and used as a cancer biomarker. However, the contribution of hTR to tumorigenesis remains elusive. In this study, we assessed the tumor-promoting properties of hTR using a natural virus/host model of herpesvirus-induced tumorigenesis. This avian herpesvirus encodes a telomerase RNA subunit (vTR) that plays a crucial role in viral tumorigenesis and shares all conserved functional domains with hTR. Our data revealed that vTR and cellular TRs of humans and chickens possess host-specific anti-apoptotic functions. This provides important translational insights into therapeutic strategies, as inhibition of apoptosis is crucial for tumorigenesis.
PubMed: 37754662
DOI: 10.1128/spectrum.01887-23 -
Frontiers in Immunology 2023Infectious Bursal Disease Virus (IBDV) causes immunosuppression in chickens. While B-cell destruction is the main cause of humoral immunosuppression, bursal T cells from...
CD4TGFβ cells infiltrated the bursa of Fabricius following IBDV infection, and correlated with a delayed viral clearance, but did not correlate with disease severity, or immunosuppression.
INTRODUCTION
Infectious Bursal Disease Virus (IBDV) causes immunosuppression in chickens. While B-cell destruction is the main cause of humoral immunosuppression, bursal T cells from IBDV-infected birds have been reported to inhibit the mitogenic response of splenocytes, indicating that some T cell subsets in the infected bursa have immunomodulatory activities. CD4CD25TGFβ cells have been recently described in chickens that have immunoregulatory properties and play a role in the pathogenesis of Marek's Disease Virus.
METHODS
To evaluate if CD4CD25TGFβ cells infiltrated the bursa of Fabricius (BF) following IBDV infection, and influenced the outcome of infection, birds were inoculated at either 2 days or 2 weeks of age with vaccine strain (228E), classic field strain (F52/70), or PBS (mock), and bursal cell populations were quantified by flow cytometry.
RESULTS
Both 228E and F52/70 led to atrophy of the BF, a significant reduction of Bu1-B cells, and a significant increase in CD4 and CD8α T cells in the BF, but only F52/70 caused suppression of immune responses to a test antigen in younger birds, and clinical signs in older birds. Virus was cleared from the BF more rapidly in younger birds than older birds. An infiltration of CD4CD25T cells into the BF, and elevated expression of bursal TGFβ-1 mRNA was observed at all time points following infection, irrespective of the strain or age of the birds, but CD4TGFβcells and CD4CD25TGFβ cells only appeared in the BF at 28 dpi in younger birds. In older birds, CD4TGFβ cells and CD4CD25TGFβ cells were present at earlier time points, from 7dpi following 228E infection, and from 14 and 28 dpi following F52/70 infection, respectively.
DISCUSSION
Our data suggest that an earlier infiltration of CD4TGFβ cells into the BF correlated with a delayed clearance of virus. However, the influx of CD4TGFβ cells and CD4CD25TGFβ into the BF did not correlate with increased pathogenicity, or immunosuppression.
Topics: Animals; Bursa of Fabricius; Chickens; Immunosuppression Therapy; Infectious bursal disease virus; Transforming Growth Factor beta
PubMed: 37744374
DOI: 10.3389/fimmu.2023.1197746 -
Journal of Virology Oct 2023Marek's disease virus (MDV) is a ubiquitous chicken pathogen that inflicts a large economic burden on the poultry industry, despite worldwide vaccination programs. MDV...
Marek's disease virus (MDV) is a ubiquitous chicken pathogen that inflicts a large economic burden on the poultry industry, despite worldwide vaccination programs. MDV is only partially controlled by available vaccines, and the virus retains the ability to replicate and spread between vaccinated birds. Following an initial infection, MDV enters a latent state and integrates into host telomeres and this may be a prerequisite for malignant transformation, which is usually fatal. To understand the mechanism that underlies the dynamic relationship between integrated-latent and reactivated MDV, we have characterized integrated MDV (iMDV) genomes and their associated telomeres. This revealed a single orientation among iMDV genomes and the loss of some terminal sequences that is consistent with integration by homology-directed recombination and excision via a telomere-loop-mediated process.
Topics: Animals; Chickens; Genome, Viral; Herpesvirus 2, Gallid; Homologous Recombination; Marek Disease; Poultry Diseases; Telomere; Viral Vaccines; Virus Activation; Virus Latency; Virus Integration
PubMed: 37737586
DOI: 10.1128/jvi.00716-23 -
BioRxiv : the Preprint Server For... Jan 2024Current strategies to understand the molecular basis of Marek's disease virus (MDV) virulence primarily consist of cataloguing divergent nucleotides between strains with...
Current strategies to understand the molecular basis of Marek's disease virus (MDV) virulence primarily consist of cataloguing divergent nucleotides between strains with different phenotypes. However, each MDV strain is typically represented by a single consensus genome despite the confirmed existence of mixed viral populations. To assess the reliability of single-consensus interstrain genomic comparisons, we obtained two additional consensus genomes of vaccine strain CVI988 (Rispens) and two additional consensus genomes of the very virulent strain Md5 by sequencing viral stocks and cultured field isolates. In conjunction with the published genomes of CVI988 and Md5, this allowed us to perform 3-way comparisons between consensus genomes of the same strain. We found that consensus genomes of CVI988 can vary in as many as 236 positions involving 13 open reading frames (ORFs). In contrast, we found that Md5 genomes varied only in 11 positions involving a single ORF. Phylogenomic analyses showed all three Md5 consensus genomes clustered closely together, while also showing that CVI988 diverged from CVI988 and CVI988 . Comparison of CVI988 consensus genomes revealed 19 SNPs in the unique regions of CVI988 that were not present in either CVI988 or CVI988 . Finally, we evaluated the genomic heterogeneity of CVI988 and Md5 populations by identifying positions with >2% read support for alternative alleles in two ultra-deeply sequenced samples. We were able to confirm that both populations of CVI988 and Md5 were mixed, exhibiting a total of 29 and 27 high-confidence minor variant positions, respectively. We did not find any evidence of minor variants in the positions corresponding to the 19 SNPs in the unique regions of CVI988 . Taken together, our findings confirm that consensus genomes of the same strain of MDV can vary and suggest that multiple consensus genomes per strain are needed in order to maximize the accuracy of interstrain genomic comparisons.
PubMed: 37732198
DOI: 10.1101/2023.09.04.556264 -
Social Science & Medicine (1982) Oct 2023Maternal influenza and pertussis immunisation is crucial for protecting mothers during pregnancy and their babies in the first weeks of life against severe disease. We...
BACKGROUND
Maternal influenza and pertussis immunisation is crucial for protecting mothers during pregnancy and their babies in the first weeks of life against severe disease. We examined geospatial variation in maternal immunisation coverage among pregnant women in Aotearoa New Zealand and its health equity implications.
METHOD
We constructed a retrospective cohort including all pregnant women who delivered between 01 January 2013 and 31 December 2020 using administrative health datasets. Our outcomes were receipt of influenza or pertussis vaccine in any one of three relevant national databases (e.g. National Immunisation Register, Proclaims, or Pharmaceutical collection) during the eligible pregnancy.
RESULTS
Data from our retrospective cohort study show significant regional variation in maternal immunisation coverage for both influenza and pertussis from 2013 to 2020. Maximal coverage was around 50% in the best performing regions, which means that half of the women who were pregnant (183,737 women) were not protected. In addition, we found significant spatio-temporal variation and clustering of immunisation coverage. Our findings are interactively available to explore here: https://geohealthlab.shinyapps.io/hapumama/ CONCLUSION: Our study is one of the first to examine spatial variation in maternal vaccination coverage in pregnant women at a national level over space and time. This provides powerful tools to measure the impact of interventions to improve coverage at national and regional levels, with specific reference to inequities between ethnic groups, likely applicable to similar settings internationally.
PubMed: 37722144
DOI: 10.1016/j.socscimed.2023.116228 -
Heart (British Cardiac Society) Jan 2024To test the hypothesis that in recipients of primary prophylactic implantable cardioverter-defibrillators (ICDs), the non-planarity of ECG vector loops predicts (a)...
OBJECTIVE
To test the hypothesis that in recipients of primary prophylactic implantable cardioverter-defibrillators (ICDs), the non-planarity of ECG vector loops predicts (a) deaths despite ICD protection and (b) appropriate ICD shocks.
METHODS
Digital pre-implant ECGs were collected in 1948 ICD recipients: 21.4% females, median age 65 years, 61.5% ischaemic heart disease (IHD). QRS and T wave three-dimensional loops were constructed using singular value decomposition that allowed to measure the vector loop planarity. The non-planarity, that is, the twist of the three-dimensional loops out of a single plane, was related to all-cause mortality (n=294; 15.3% females; 68.7% IHD) and appropriate ICD shocks (n=162; 10.5% females; 87.7% IHD) during 5-year follow-up after device implantation. Using multivariable Cox regression, the predictive power of QRS and T wave non-planarity was compared with that of age, heart rate, left ventricular ejection fraction, QRS duration, spatial QRS-T angle, QTc interval and T-peak to T-end interval.
RESULTS
QRS non-planarity was significantly (p<0.001) associated with follow-up deaths despite ICD protection with HR of 1.339 (95% CI 1.165 to 1.540) but was only univariably associated with appropriate ICD shocks. Non-planarity of the T wave loop was the only ECG-derived index significantly (p<0.001) associated with appropriate ICD shocks with multivariable Cox regression HR of 1.364 (1.180 to 1.576) but was not associated with follow-up mortality.
CONCLUSIONS
The analysed data suggest that QRS and T wave non-planarity might offer distinction between patients who are at greater risk of death despite ICD protection and those who are likely to use the defibrillator protection.
Topics: Female; Humans; Aged; Male; Defibrillators, Implantable; Stroke Volume; Ventricular Function, Left; Arrhythmias, Cardiac; Electrocardiography; Myocardial Ischemia; Coronary Artery Disease; Death, Sudden, Cardiac; Risk Factors
PubMed: 37714697
DOI: 10.1136/heartjnl-2023-322878 -
NPJ Parkinson's Disease Sep 2023
PubMed: 37704671
DOI: 10.1038/s41531-023-00560-7 -
NPJ Parkinson's Disease Sep 2023The Global Parkinson's Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in...
The Global Parkinson's Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia.
PubMed: 37699923
DOI: 10.1038/s41531-023-00533-w -
Cancers Sep 2023Anti-EGFR antibodies combined with chemotherapy doublets are a cornerstone of the upfront treatment of colorectal cancer. RAS and BRAF mutations are established negative...
The Impact of Sidedness on the Efficacy of Anti-EGFR-Based First-Line Chemotherapy in Advanced Colorectal Cancer Patients in Real-Life Setting-A Nation-Wide Retrospective Analysis (RACER).
Anti-EGFR antibodies combined with chemotherapy doublets are a cornerstone of the upfront treatment of colorectal cancer. RAS and BRAF mutations are established negative predictive factors for such therapy. The primary tumour located in the proximal colon has recently emerged as another negative predictive factor. We have conducted a retrospective multicentre study to collect data on real-world population characteristics, practice patterns, and outcomes in patients with metastatic colorectal cancer treated in a first-line setting with either cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI chemotherapy. The presented analysis focuses on the impact of the primary tumour location. 126 of 842 patients analysed (15.0%) had proximal primary. It was associated with a lower BMI at diagnosis, mucinous histology, and peritoneal metastases. It was also associated with inferior treatment outcomes in terms of response ratio: 59.4% vs. 74.22% (odds ratio [OR] 0.51, 95% CI 0.33-0.78, = 0.010), and median depth of response: -36.7% vs. -50.0% ( = 0.038). There was only a borderline non-significant trend for inferior PFS in patients with proximal tumours. OS data was incomplete. The presented analysis confirms the negative impact of tumour sidedness on the efficacy of an upfront anti-EGFR-chemotherapy combination and provides valuable data on real-world population characteristics.
PubMed: 37686636
DOI: 10.3390/cancers15174361 -
Molecular Therapy Oncolytics Sep 2023Unraveling the complexities of the tumor microenvironment (TME) and its correlation with responsiveness to immunotherapy has become a main focus in overcoming resistance...
Unraveling the complexities of the tumor microenvironment (TME) and its correlation with responsiveness to immunotherapy has become a main focus in overcoming resistance to such treatments. Targeting tumor-intrinsic retinoic acid-inducible gene-I (RIG-I), a sensor for viral RNA, was shown to transform the TME from an immunogenically "cold" state to an inflamed, "hot" lesion, which we demonstrated previously to be a crucial mediator of the efficacy of immune checkpoint inhibition with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4). In this study, we focus on the chimeric oncolytic virus vesicular stomatitis virus (VSV)-Newcastle disease virus (NDV), comprised of genetic components of VSV and NDV, and we investigate its utility to support tumor-intrinsic RIG-I-dependent therapy with anti-CTLA-4. Overall, we demonstrate that treatment with VSV-NDV efficiently delays tumor growth and significantly prolongs survival in a murine model of malignant melanoma, which was further enhanced in combination with anti-CTLA-4. Although the direct oncolytic and pro-inflammatory effects of VSV-NDV therapy were independent of RIG-I activation, the synergism with anti-CTLA-4 therapy and associated activation of tumor-specific T cells was critically dependent on active RIG-I signaling in tumor cells. This work highlights the therapeutic value of utilizing an immune-stimulatory oncolytic virus to sensitize tumors to immune checkpoint inhibition.
PubMed: 37654972
DOI: 10.1016/j.omto.2023.08.001