Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells
Human adenoviruses (HAdV) cause a variety of infections in human hosts, from self-limited upper respiratory tract infections in otherwise healthy people to fulminant pneumonia and death in immunocompromised patients. Many HAdV enter polarized epithelial cells by using the primary receptor, the Coxsa...
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MDPI AG
2021-12-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/1/13 |
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| author | James M. Readler Meghan R. Burke Priyanka Sharma Katherine J. D. A. Excoffon Abimbola O. Kolawole |
| author_facet | James M. Readler Meghan R. Burke Priyanka Sharma Katherine J. D. A. Excoffon Abimbola O. Kolawole |
| author_sort | James M. Readler |
| collection | DOAJ |
| description | Human adenoviruses (HAdV) cause a variety of infections in human hosts, from self-limited upper respiratory tract infections in otherwise healthy people to fulminant pneumonia and death in immunocompromised patients. Many HAdV enter polarized epithelial cells by using the primary receptor, the Coxsackievirus and adenovirus receptor (CAR). Recently published data demonstrate that a potent neutrophil (PMN) chemoattractant, interleukin-8 (IL-8), stimulates airway epithelial cells to increase expression of the apical isoform of CAR (CAR<sup>Ex8</sup>), which results in increased epithelial HAdV type 5 (HAdV5) infection. However, the mechanism for PMN-enhanced epithelial HAdV5 transduction remains unclear. In this manuscript, the molecular mechanisms behind PMN mediated enhancement of epithelial HAdV5 transduction are characterized using an MDCK cell line that stably expresses human CAR<sup>Ex8</sup> under a doxycycline inducible promoter (MDCK-CAR<sup>Ex8</sup> cells). Contrary to our hypothesis, PMN exposure does not enhance HAdV5 entry by increasing CAR<sup>Ex8</sup> expression nor through activation of non-specific epithelial endocytic pathways. Instead, PMN serine proteases are responsible for PMN-mediated enhancement of HAdV5 transduction in MDCK-CAR<sup>Ex8</sup> cells. This is evidenced by reduced transduction upon inhibition of PMN serine proteases and increased transduction upon exposure to exogenous human neutrophil elastase (HNE). Furthermore, HNE exposure activates epithelial autophagic flux, which, even when triggered through other mechanisms, results in a similar enhancement of epithelial HAdV5 transduction. Inhibition of F-actin with cytochalasin D partially attenuates PMN mediated enhancement of HAdV transduction. Taken together, these findings suggest that HAdV5 can leverage innate immune responses to establish infections. |
| first_indexed | 2024-03-10T00:21:58Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T00:21:58Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-98b75f19b4644b61b48bd741251a86932023-11-23T15:40:46ZengMDPI AGViruses1999-49152021-12-011411310.3390/v14010013Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial CellsJames M. Readler0Meghan R. Burke1Priyanka Sharma2Katherine J. D. A. Excoffon3Abimbola O. Kolawole4Department of Biological Sciences, Wright State University, Dayton, OH 45435, USADepartment of Biological Sciences, Wright State University, Dayton, OH 45435, USADepartment of Biological Sciences, Wright State University, Dayton, OH 45435, USADepartment of Biological Sciences, Wright State University, Dayton, OH 45435, USADepartment of Biological Sciences, Wright State University, Dayton, OH 45435, USAHuman adenoviruses (HAdV) cause a variety of infections in human hosts, from self-limited upper respiratory tract infections in otherwise healthy people to fulminant pneumonia and death in immunocompromised patients. Many HAdV enter polarized epithelial cells by using the primary receptor, the Coxsackievirus and adenovirus receptor (CAR). Recently published data demonstrate that a potent neutrophil (PMN) chemoattractant, interleukin-8 (IL-8), stimulates airway epithelial cells to increase expression of the apical isoform of CAR (CAR<sup>Ex8</sup>), which results in increased epithelial HAdV type 5 (HAdV5) infection. However, the mechanism for PMN-enhanced epithelial HAdV5 transduction remains unclear. In this manuscript, the molecular mechanisms behind PMN mediated enhancement of epithelial HAdV5 transduction are characterized using an MDCK cell line that stably expresses human CAR<sup>Ex8</sup> under a doxycycline inducible promoter (MDCK-CAR<sup>Ex8</sup> cells). Contrary to our hypothesis, PMN exposure does not enhance HAdV5 entry by increasing CAR<sup>Ex8</sup> expression nor through activation of non-specific epithelial endocytic pathways. Instead, PMN serine proteases are responsible for PMN-mediated enhancement of HAdV5 transduction in MDCK-CAR<sup>Ex8</sup> cells. This is evidenced by reduced transduction upon inhibition of PMN serine proteases and increased transduction upon exposure to exogenous human neutrophil elastase (HNE). Furthermore, HNE exposure activates epithelial autophagic flux, which, even when triggered through other mechanisms, results in a similar enhancement of epithelial HAdV5 transduction. Inhibition of F-actin with cytochalasin D partially attenuates PMN mediated enhancement of HAdV transduction. Taken together, these findings suggest that HAdV5 can leverage innate immune responses to establish infections.https://www.mdpi.com/1999-4915/14/1/13adenovirusentryautophagyneutrophilhuman neutrophil elastaseMDCK epithelial cells |
| spellingShingle | James M. Readler Meghan R. Burke Priyanka Sharma Katherine J. D. A. Excoffon Abimbola O. Kolawole Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells Viruses adenovirus entry autophagy neutrophil human neutrophil elastase MDCK epithelial cells |
| title | Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells |
| title_full | Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells |
| title_fullStr | Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells |
| title_full_unstemmed | Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells |
| title_short | Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells |
| title_sort | adenovirus co opts neutrophilic inflammation to enhance transduction of epithelial cells |
| topic | adenovirus entry autophagy neutrophil human neutrophil elastase MDCK epithelial cells |
| url | https://www.mdpi.com/1999-4915/14/1/13 |
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