Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and Pathogenesis
Machupo virus (MACV), a member of the <i>Arenaviridae</i> family and causative agent of Bolivian hemorrhagic fever, results in lethality rates of 25–35% in humans. Mice lacking the signal transducer and activator of transcription 1 (STAT-1<sup>−/−</sup>) have previously been...
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2025-07-01
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| Online Access: | https://www.mdpi.com/1999-4915/17/7/996 |
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| author | Stephanie R. Monticelli Ana I. Kuehne Russell R. Bakken Susan R. Coyne Kenise D. Lewis Jo Lynne W. Raymond Xiankun Zeng Joshua B. Richardson Zebulon Lapoint Jennifer L. Williams Christopher P. Stefan Jeffrey R. Kugelman Jeffrey W. Koehler Andrew S. Herbert |
| author_facet | Stephanie R. Monticelli Ana I. Kuehne Russell R. Bakken Susan R. Coyne Kenise D. Lewis Jo Lynne W. Raymond Xiankun Zeng Joshua B. Richardson Zebulon Lapoint Jennifer L. Williams Christopher P. Stefan Jeffrey R. Kugelman Jeffrey W. Koehler Andrew S. Herbert |
| author_sort | Stephanie R. Monticelli |
| collection | DOAJ |
| description | Machupo virus (MACV), a member of the <i>Arenaviridae</i> family and causative agent of Bolivian hemorrhagic fever, results in lethality rates of 25–35% in humans. Mice lacking the signal transducer and activator of transcription 1 (STAT-1<sup>−/−</sup>) have previously been shown to succumb to MACV infection within 7–8 days via the intraperitoneal route. Despite these reports, we observed partial lethality in STAT-1<sup>−/−</sup> mice following challenge with wild-type MACV. Serial sampling studies to evaluate the temporal progression of infection and pathologic changes after challenge revealed a two-phase disease course. The first phase was characterized by viral load and pathological lesions in the spleen, liver, and kidney followed by a second, lethal phase, defined by high viral titers and inflammation in the brain and spinal cord resulting in neurological manifestations and subsequent mortality. Tissue adaptation in the brains of challenged STAT-1<sup>−/−</sup> mice resulted in a fully lethal model in STAT-1<sup>−/−</sup> mice (mouse-adapted; maMACV). A similar two-phase disease course was observed following maMACV challenge, but more rapid dissemination of the virus to the brain and overall pathology in this region was observed. The outcome of these studies is a lethal small rodent model of MACV that recapitulates many aspects of human disease. |
| format | Article |
| id | doaj-art-bf1d05dc4702498a8f0f28f9fa8923a8 |
| institution | Kabale University |
| issn | 1999-4915 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj-art-bf1d05dc4702498a8f0f28f9fa8923a82025-08-20T03:56:46ZengMDPI AGViruses1999-49152025-07-0117799610.3390/v17070996Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and PathogenesisStephanie R. Monticelli0Ana I. Kuehne1Russell R. Bakken2Susan R. Coyne3Kenise D. Lewis4Jo Lynne W. Raymond5Xiankun Zeng6Joshua B. Richardson7Zebulon Lapoint8Jennifer L. Williams9Christopher P. Stefan10Jeffrey R. Kugelman11Jeffrey W. Koehler12Andrew S. Herbert13Viral Immunology Branch, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USAThe Geneva Foundation, Tacoma, WA 20817, USAThe Geneva Foundation, Tacoma, WA 20817, USADevelopmental Diagnostics Branch, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USAChenega Corporation, Anchorage, AK 99503, USAPathology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USAPathology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USACherokee Nation Integrated Health, Catoosa, OK 74015, USACherokee Nation Integrated Health, Catoosa, OK 74015, USACherokee Nation Integrated Health, Catoosa, OK 74015, USADevelopmental Diagnostics Branch, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USACenter for Genome Science, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USAOperational Diagnostics Branch, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USAThe Geneva Foundation, Tacoma, WA 20817, USAMachupo virus (MACV), a member of the <i>Arenaviridae</i> family and causative agent of Bolivian hemorrhagic fever, results in lethality rates of 25–35% in humans. Mice lacking the signal transducer and activator of transcription 1 (STAT-1<sup>−/−</sup>) have previously been shown to succumb to MACV infection within 7–8 days via the intraperitoneal route. Despite these reports, we observed partial lethality in STAT-1<sup>−/−</sup> mice following challenge with wild-type MACV. Serial sampling studies to evaluate the temporal progression of infection and pathologic changes after challenge revealed a two-phase disease course. The first phase was characterized by viral load and pathological lesions in the spleen, liver, and kidney followed by a second, lethal phase, defined by high viral titers and inflammation in the brain and spinal cord resulting in neurological manifestations and subsequent mortality. Tissue adaptation in the brains of challenged STAT-1<sup>−/−</sup> mice resulted in a fully lethal model in STAT-1<sup>−/−</sup> mice (mouse-adapted; maMACV). A similar two-phase disease course was observed following maMACV challenge, but more rapid dissemination of the virus to the brain and overall pathology in this region was observed. The outcome of these studies is a lethal small rodent model of MACV that recapitulates many aspects of human disease.https://www.mdpi.com/1999-4915/17/7/996arenavirusSTAT1Machupo virusarenavirus mouse models |
| spellingShingle | Stephanie R. Monticelli Ana I. Kuehne Russell R. Bakken Susan R. Coyne Kenise D. Lewis Jo Lynne W. Raymond Xiankun Zeng Joshua B. Richardson Zebulon Lapoint Jennifer L. Williams Christopher P. Stefan Jeffrey R. Kugelman Jeffrey W. Koehler Andrew S. Herbert Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and Pathogenesis Viruses arenavirus STAT1 Machupo virus arenavirus mouse models |
| title | Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and Pathogenesis |
| title_full | Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and Pathogenesis |
| title_fullStr | Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and Pathogenesis |
| title_full_unstemmed | Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and Pathogenesis |
| title_short | Characterization of a STAT-1 Knockout Mouse Model for Machupo Virus Infection and Pathogenesis |
| title_sort | characterization of a stat 1 knockout mouse model for machupo virus infection and pathogenesis |
| topic | arenavirus STAT1 Machupo virus arenavirus mouse models |
| url | https://www.mdpi.com/1999-4915/17/7/996 |
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