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Newcastle Disease Virus Induces Profound Lymphoid Depletion with Different Patterns of Necroptosis, Necrosis, and Oxidative DNA Damage in Bursa, Spleen, and Other Lymphoid Tissues

by Mohammad Rabiei, Milton M. McAllister, Natalie R. Gassman, Kevin J. Lee, Sydney Acton, Dieter Liebhart, Wai Yee Low and Farhid Hemmatzadeh

Pathogens 2024, 13(8), 619; https://doi.org/10.3390/pathogens13080619 - 26 Jul 2024

Cited by 1 | Viewed by 1900

Abstract

This study delves into the pathogenesis of virulent genotype VII strains of the Newcastle disease virus (NDV), focusing on experimentally infected birds. Predominant and consistent lesions observed include bursal atrophy and extensive depletion of all lymphoid tissues. Immunohistochemistry (IHC) analysis, targeting apoptosis (Caspase-3), necroptosis (MLKL), and NDV markers, indicates that bursal atrophy is linked to a non-apoptotic programmed cell death pathway known as “necroptosis”. Repair assisted damage detection (RADD) of the bursa reveal oxidative DNA damage patterns consistent with programmed cell death, aligning with MLKL expression. Contrastingly, in the spleen, our findings suggest that necrosis (non-programmed cell death) predominantly contributes to lymphoid depletion. This conclusion is supported by evidence of karyorrhexis, fibrinous inflammation, RADD analyses, and IHC. Moreover, in addition to being pathogenic in its own right, NDV caused extensive and rapid lymphoid depletion that should be expected to contribute to profound immunosuppression. The elucidation of necroptosis in NDV-infected chickens provides a good rationale to investigate this mechanism in other paramyxoviral diseases such as human measles. Full article

(This article belongs to the Special Issue Host Immune Responses to RNA Viruses, 2nd Edition)

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11 pages, 1382 KB

Open AccessArticle

Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans

by Kimiko L. Krieger, Jie H. Gohlke, Kevin J. Lee, Danthasinghe Waduge Badrajee Piyarathna, Patricia D. Castro, Jeffrey A. Jones, Michael M. Ittmann, Natalie R. Gassman and Arun Sreekumar

Cancers 2022, 14(4), 1012; https://doi.org/10.3390/cancers14041012 - 17 Feb 2022

Cited by 13 | Viewed by 2604

Abstract

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues. Tissue microarrays with matched tumor-benign adjacent pairs from 77 AA and EA PCa patients were analyzed for abasic sites, oxidative lesions, crosslinks, and uracil content using the Repair Assisted Damage Detection (RADD) assay. Our analysis revealed that AA PCa, overall, have more DNA damage than EA PCa. Increased uracil and pyrimidine lesions occurred in AA tumors, while EA tumors had more oxidative lesions. AA PCa have higher levels of UMP and folate cycle metabolites than their EA counterparts. AA PCa showed higher levels of UNG, the uracil-specific glycosylase, than EA, despite uracil lesions being retained within the genome. AA patients also had lower levels of the base excision repair protein XRCC1. These results indicate dysfunction in the base excision repair pathway in AA tumors. Further, these findings reveal how metabolic rewiring in AA PCa drives biological disparities and identifies a targetable axis for cancer therapeutics. Full article

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15 pages, 2538 KB

Open AccessArticle

Associations between DNA Damage and PD-L1 Expression in Ovarian Cancer, a Potential Biomarker for Clinical Response

by Elise K. Mann, Kevin J. Lee, Dongquan Chen, Luciana Madeira da Silva, Valeria L. Dal Zotto, Jennifer Scalici and Natalie R. Gassman

Biology 2021, 10(5), 385; https://doi.org/10.3390/biology10050385 - 29 Apr 2021

Cited by 10 | Viewed by 3478

Abstract

Programmed death ligand-1 (PD-L1) inhibitors are currently under investigation as a potential treatment option for ovarian cancer. Although this therapy has shown promise, its efficacy is highly variable among patients. Evidence suggests that genomic instability influences the expression of PD-L1, but little is known about this relationship in ovarian cancer. To examine the relationship between PD-L1 expression and genomic instability, we measured DNA damage using Repair Assisted Damage Detection (RADD). We then correlated the presence of persistent DNA damage in the ovarian tumor with protein expression of PD-L1 using immunohistochemistry. Ovarian tumors showed a high prevalence of oxidative DNA damage. As the level of oxidative DNA damage increased, we saw a significant correlation with PD-L1 expression. The highest correlation between DNA damage and PD-L1 expression was observed for mucinous ovarian tumors (r = 0.82), but a strong correlation was also observed for high grade serous and endometrioid tumors (r = 0.67 and 0.69, respectively). These findings link genomic instability to PD-L1 protein expression in ovarian cancer and suggest that persistent DNA damage can be used as a potential biomarker for patient selection for immunotherapy treatment. Full article

(This article belongs to the Special Issue Mechanisms of DNA Repair in the Context of Transcription, Replication and Recombination)

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