Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis
Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively....
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | Virology Journal |
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| Online Access: | http://link.springer.com/article/10.1186/s12985-017-0908-0 |
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| author | Ellen Brisse Maya Imbrechts Tania Mitera Jessica Vandenhaute Carine H. Wouters Robert Snoeck Graciela Andrei Patrick Matthys |
| author_facet | Ellen Brisse Maya Imbrechts Tania Mitera Jessica Vandenhaute Carine H. Wouters Robert Snoeck Graciela Andrei Patrick Matthys |
| author_sort | Ellen Brisse |
| collection | DOAJ |
| description | Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively. Clinical manifestations of both forms are frequently preceded by a viral infection, predominantly with herpesviruses. The exact role of the viral infection in the development of the hemophagocytic syndrome remains to be further elucidated. Methods We utilized a recently developed murine model of cytomegalovirus-associated secondary HLH and dissected the respective contributions of lytic viral replication and immunopathology in its pathogenesis. Results HLH-like disease only developed in cytomegalovirus-susceptible mouse strains unable to clear the virus, but the severity of symptoms was not correlated to the infectious viral titer. Lytic viral replication and sustained viremia played an essential part in the pathogenesis since abortive viral infection was insufficient to induce a full-blown HLH-like syndrome. Nonetheless, a limited set of symptoms, in particular anemia, thrombocytopenia and elevated levels of soluble CD25, appeared less dependent of the viral replication but rather mediated by the host’s immune response, as corroborated by immunosuppressive treatment of infected mice with dexamethasone. Conclusion Both virus-mediated pathology and immunopathology cooperate in the pathogenesis of full-blown virus-associated secondary HLH and are closely entangled. A certain level of viremia appears necessary to elicit the characteristic HLH-like symptoms in the model. |
| first_indexed | 2024-12-22T04:21:02Z |
| format | Article |
| id | doaj.art-024fbf8963514ce3a52f9f9be555a033 |
| institution | Directory Open Access Journal |
| issn | 1743-422X |
| language | English |
| last_indexed | 2024-12-22T04:21:02Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Virology Journal |
| spelling | doaj.art-024fbf8963514ce3a52f9f9be555a0332022-12-21T18:39:17ZengBMCVirology Journal1743-422X2017-12-0114111610.1186/s12985-017-0908-0Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosisEllen Brisse0Maya Imbrechts1Tania Mitera2Jessica Vandenhaute3Carine H. Wouters4Robert Snoeck5Graciela Andrei6Patrick Matthys7Laboratory of Immunobiology, Rega Institute, Department of Microbiology and Immunology, KU LeuvenLaboratory of Immunobiology, Rega Institute, Department of Microbiology and Immunology, KU LeuvenLaboratory of Immunobiology, Rega Institute, Department of Microbiology and Immunology, KU LeuvenLaboratory of Immunobiology, Rega Institute, Department of Microbiology and Immunology, KU LeuvenLaboratory of Pediatric Immunology, Department of Microbiology and Immunology, University Hospital Gasthuisberg, KU LeuvenLaboratory of Virology and Chemotherapy, Rega Institute, Department of Microbiology and Immunology, KU LeuvenLaboratory of Virology and Chemotherapy, Rega Institute, Department of Microbiology and Immunology, KU LeuvenLaboratory of Immunobiology, Rega Institute, Department of Microbiology and Immunology, KU LeuvenAbstract Background Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively. Clinical manifestations of both forms are frequently preceded by a viral infection, predominantly with herpesviruses. The exact role of the viral infection in the development of the hemophagocytic syndrome remains to be further elucidated. Methods We utilized a recently developed murine model of cytomegalovirus-associated secondary HLH and dissected the respective contributions of lytic viral replication and immunopathology in its pathogenesis. Results HLH-like disease only developed in cytomegalovirus-susceptible mouse strains unable to clear the virus, but the severity of symptoms was not correlated to the infectious viral titer. Lytic viral replication and sustained viremia played an essential part in the pathogenesis since abortive viral infection was insufficient to induce a full-blown HLH-like syndrome. Nonetheless, a limited set of symptoms, in particular anemia, thrombocytopenia and elevated levels of soluble CD25, appeared less dependent of the viral replication but rather mediated by the host’s immune response, as corroborated by immunosuppressive treatment of infected mice with dexamethasone. Conclusion Both virus-mediated pathology and immunopathology cooperate in the pathogenesis of full-blown virus-associated secondary HLH and are closely entangled. A certain level of viremia appears necessary to elicit the characteristic HLH-like symptoms in the model.http://link.springer.com/article/10.1186/s12985-017-0908-0Hemophagocytic lymphohistiocytosisHLHmacrophage activation syndromeMASmouse modelmouse cytomegalovirus |
| spellingShingle | Ellen Brisse Maya Imbrechts Tania Mitera Jessica Vandenhaute Carine H. Wouters Robert Snoeck Graciela Andrei Patrick Matthys Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis Virology Journal Hemophagocytic lymphohistiocytosis HLH macrophage activation syndrome MAS mouse model mouse cytomegalovirus |
| title | Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis |
| title_full | Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis |
| title_fullStr | Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis |
| title_full_unstemmed | Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis |
| title_short | Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis |
| title_sort | lytic viral replication and immunopathology in a cytomegalovirus induced mouse model of secondary hemophagocytic lymphohistiocytosis |
| topic | Hemophagocytic lymphohistiocytosis HLH macrophage activation syndrome MAS mouse model mouse cytomegalovirus |
| url | http://link.springer.com/article/10.1186/s12985-017-0908-0 |
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