التفاصيل البيبلوغرافية
| العنوان: |
Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis. |
| المؤلفون: |
Guo, Kejun, Shen, Guannan, Kibbie, Jon, Gonzalez, Tania, Dillon, Stephanie M., Smith, Harry A., Cooper, Emily H., Lavender, Kerry, Hasenkrug, Kim J., Sutter, Kathrin, Dittmer, Ulf, Kroehl, Miranda, Kechris, Katerina, Wilson, Cara C., Santiago, Mario L. |
| المصدر: |
PLoS Pathogens; 10/16/2020, Vol. 16 Issue 10, p1-29, 29p |
| مصطلحات موضوعية: |
PATHOLOGY, TYPE I interferons, HIV, GENE expression profiling, T cells, INTERFERON receptors, BIOMARKERS |
| مستخلص: |
The Type I Interferons (IFN-Is) are innate antiviral cytokines that include 12 different IFNα subtypes and IFNβ that signal through the IFN-I receptor (IFNAR), inducing hundreds of IFN-stimulated genes (ISGs) that comprise the 'interferome'. Quantitative differences in IFNAR binding correlate with antiviral activity, but whether IFN-Is exhibit qualitative differences remains controversial. Moreover, the IFN-I response is protective during acute HIV-1 infection, but likely pathogenic during the chronic stages. To gain a deeper understanding of the IFN-I response, we compared the interferomes of IFNα subtypes dominantly-expressed in HIV-1-exposed plasmacytoid dendritic cells (1, 2, 5, 8 and 14) and IFNβ in the earliest cellular targets of HIV-1 infection. Primary gut CD4 T cells from 3 donors were treated for 18 hours ex vivo with individual IFN-Is normalized for IFNAR signaling strength. Of 1,969 IFN-regulated genes, 246 'core ISGs' were induced by all IFN-Is tested. However, many IFN-regulated genes were not shared between the IFNα subtypes despite similar induction of canonical antiviral ISGs such as ISG15, RSAD2 and MX1, formally demonstrating qualitative differences between the IFNα subtypes. Notably, IFNβ induced a broader interferome than the individual IFNα subtypes. Since IFNβ, and not IFNα, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNβ-specific ISGs from colon pinch biopsies of HIV-1-uninfected (n = 13) versus age- and gender-matched, antiretroviral-therapy naïve persons with HIV-1 (PWH; n = 19). Core ISGs linked to inflammation, T cell activation and immune exhaustion were elevated in PWH, positively correlated with plasma lipopolysaccharide (LPS) levels and gut IFNβ levels, and negatively correlated with gut CD4 T cell frequencies. In sharp contrast, IFNβ-specific ISGs linked to protein translation and anti-inflammatory responses were significantly downregulated in PWH, negatively correlated with gut IFNβ and LPS, and positively correlated with plasma IL6 and gut CD4 T cell frequencies. Our findings reveal qualitative differences in interferome induction by diverse IFN-Is and suggest potential mechanisms for how IFNβ may drive HIV-1 pathogenesis in the gut. Author summary: The Type I Interferons (IFN-Is) serve as the first line of defense against viral infections. IFN-Is are evolutionarily diverse, with 12 distinct IFNα subtypes and IFNβ in humans. All IFN-Is bind to the same receptor, but it remains unclear whether distinct IFN-Is will trigger the same set of IFN-stimulated genes. Here, we provide evidence that diverse IFN-Is altered gene expression in gut CD4 T cells in different ways. Specifically, IFNβ induced a broader gene expression profile than individual IFNα subtypes. Genes induced by IFNβ in gut CD4 T cells ex vivo were downregulated in the gut during chronic HIV-1 infection. This downregulation correlated with markers of inflammation and immune dysfunction. Our data unravel qualitative differences between the IFN-Is and suggest a complex picture of how IFNβ may be driving HIV-1 pathogenesis in the gastrointestinal tract. [ABSTRACT FROM AUTHOR] |
|
Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder