SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways
Transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Pathogens |
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| Online Access: | https://www.mdpi.com/2076-0817/11/2/257 |
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| author | Hussin A. Rothan Pratima Kumari Shannon Stone Janhavi P. Natekar Komal Arora Tabassum T. Auroni Mukesh Kumar |
| author_facet | Hussin A. Rothan Pratima Kumari Shannon Stone Janhavi P. Natekar Komal Arora Tabassum T. Auroni Mukesh Kumar |
| author_sort | Hussin A. Rothan |
| collection | DOAJ |
| description | Transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of SARS-CoV-2 within the central nervous system (CNS) of K18-hACE2 mice is associated with increased mortality; although, the mechanisms by which this occurs remain unclear. In this study, we generated primary neuronal cultures from K18-hACE2 mice to investigate the effects of a SARS-CoV-2 infection. We also evaluated the immunological response to SARS-CoV-2 infection in the CNS of K18-hACE2 mice and mouse neuronal cultures. Our data show that neuronal cultures obtained from K18-hACE2 mice are permissive to SARS-CoV-2 infection and support productive virus replication. Furthermore, SARS-CoV-2 infection upregulated the expression of genes involved in innate immunity and inflammation, including IFN-α, ISG-15, CXCL10, CCL2, IL-6 and TNF-α, in the neurons and mouse brains. In addition, we found that SARS-CoV-2 infection of neurons and mouse brains activates the ZBP1/pMLKL-regulated necroptosis pathway. Together, our data provide insights into the neuropathogenesis of SARS-CoV-2 infection in K18-hACE2 mice. |
| first_indexed | 2024-03-09T21:15:47Z |
| format | Article |
| id | doaj.art-3ec25e81495b4951859f4dc2471aea2f |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-09T21:15:47Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-3ec25e81495b4951859f4dc2471aea2f2023-11-23T21:32:50ZengMDPI AGPathogens2076-08172022-02-0111225710.3390/pathogens11020257SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic PathwaysHussin A. Rothan0Pratima Kumari1Shannon Stone2Janhavi P. Natekar3Komal Arora4Tabassum T. Auroni5Mukesh Kumar6Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USADepartment of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USADepartment of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USADepartment of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USADepartment of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USADepartment of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USADepartment of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USATransgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of SARS-CoV-2 within the central nervous system (CNS) of K18-hACE2 mice is associated with increased mortality; although, the mechanisms by which this occurs remain unclear. In this study, we generated primary neuronal cultures from K18-hACE2 mice to investigate the effects of a SARS-CoV-2 infection. We also evaluated the immunological response to SARS-CoV-2 infection in the CNS of K18-hACE2 mice and mouse neuronal cultures. Our data show that neuronal cultures obtained from K18-hACE2 mice are permissive to SARS-CoV-2 infection and support productive virus replication. Furthermore, SARS-CoV-2 infection upregulated the expression of genes involved in innate immunity and inflammation, including IFN-α, ISG-15, CXCL10, CCL2, IL-6 and TNF-α, in the neurons and mouse brains. In addition, we found that SARS-CoV-2 infection of neurons and mouse brains activates the ZBP1/pMLKL-regulated necroptosis pathway. Together, our data provide insights into the neuropathogenesis of SARS-CoV-2 infection in K18-hACE2 mice.https://www.mdpi.com/2076-0817/11/2/257COVID-19SARS-CoV-2K18-hACE2 miceneuronsneuropathogenesisinflammation |
| spellingShingle | Hussin A. Rothan Pratima Kumari Shannon Stone Janhavi P. Natekar Komal Arora Tabassum T. Auroni Mukesh Kumar SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways Pathogens COVID-19 SARS-CoV-2 K18-hACE2 mice neurons neuropathogenesis inflammation |
| title | SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways |
| title_full | SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways |
| title_fullStr | SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways |
| title_full_unstemmed | SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways |
| title_short | SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways |
| title_sort | sars cov 2 infects primary neurons from human ace2 expressing mice and upregulates genes involved in the inflammatory and necroptotic pathways |
| topic | COVID-19 SARS-CoV-2 K18-hACE2 mice neurons neuropathogenesis inflammation |
| url | https://www.mdpi.com/2076-0817/11/2/257 |
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