Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model
Invasive pulmonary aspergillosis (IPA) is a life-threatening fungal infection occurring mainly in immunocompromised patients. We recently identified IPA as an emerging co-infection with high mortality in critically ill, but otherwise immunocompetent influenza patients. The neuraminidase inhibitor os...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2021-12-01
|
| Series: | Virulence |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/21505594.2021.1974327 |
| _version_ | 1818976270348713984 |
|---|---|
| author | Laura Seldeslachts Lore Vanderbeke Astrid Fremau Agustin Reséndiz-Sharpe Cato Jacobs Bo Laeveren Tessa Ostyn Lieve Naesens Matthias Brock Frank L. Van De Veerdonk Stephanie Humblet-Baron Erik Verbeken Katrien Lagrou Joost Wauters Greetje Vande Velde |
| author_facet | Laura Seldeslachts Lore Vanderbeke Astrid Fremau Agustin Reséndiz-Sharpe Cato Jacobs Bo Laeveren Tessa Ostyn Lieve Naesens Matthias Brock Frank L. Van De Veerdonk Stephanie Humblet-Baron Erik Verbeken Katrien Lagrou Joost Wauters Greetje Vande Velde |
| author_sort | Laura Seldeslachts |
| collection | DOAJ |
| description | Invasive pulmonary aspergillosis (IPA) is a life-threatening fungal infection occurring mainly in immunocompromised patients. We recently identified IPA as an emerging co-infection with high mortality in critically ill, but otherwise immunocompetent influenza patients. The neuraminidase inhibitor oseltamivir is the current standard-of-care treatment in hospitalized influenza patients; however, its efficacy in influenza-associated pulmonary aspergillosis (IAPA) is not known. Therefore, we have established an imaging-supported double-hit mouse model to investigate the therapeutic effect of oseltamivir on the development of IAPA. Immunocompetent mice received intranasal instillation influenza A or PBS followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Oseltamivir treatment or placebo was started at day 0, day 2, or day 4. Daily monitoring included micro-computed tomography and bioluminescence imaging of pneumonia and fungal burden. Non-invasive biomarkers were complemented with imaging, molecular, immunological, and pathological analysis. Influenza virus-infected immunocompetent mice developed proven airway IPA upon co-infection with Aspergillus fumigatus, whereas non-influenza-infected mice fully cleared Aspergillus, confirming influenza as a risk factor for developing IPA. Longitudinal micro-CT showed pulmonary lesions after influenza infection worsening after Aspergillus co-infection, congruent with bioluminescence imaging and histology confirming Aspergillus pneumonia. Early oseltamivir treatment prevented severe influenza pneumonia and mitigated the development of IPA and associated mortality. A time-dependent treatment effect was consistently observed with imaging, molecular, and pathological analyses. Hence, our findings underscore the importance of initiating oseltamivir as soon as possible, to suppress influenza infection and mitigate the risk of potentially lethal IAPA disease. |
| first_indexed | 2024-12-20T16:09:11Z |
| format | Article |
| id | doaj.art-1a58bca21f2048878a27c71e670ede56 |
| institution | Directory Open Access Journal |
| issn | 2150-5594 2150-5608 |
| language | English |
| last_indexed | 2024-12-20T16:09:11Z |
| publishDate | 2021-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Virulence |
| spelling | doaj.art-1a58bca21f2048878a27c71e670ede562022-12-21T19:34:04ZengTaylor & Francis GroupVirulence2150-55942150-56082021-12-011212493250810.1080/21505594.2021.19743271974327Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine modelLaura Seldeslachts0Lore Vanderbeke1Astrid Fremau2Agustin Reséndiz-Sharpe3Cato Jacobs4Bo Laeveren5Tessa Ostyn6Lieve Naesens7Matthias Brock8Frank L. Van De Veerdonk9Stephanie Humblet-Baron10Erik Verbeken11Katrien Lagrou12Joost Wauters13Greetje Vande Velde14Biomedical MRI unit/MoSAIC, Ku LeuvenImmunology and Transplantation, Laboratory of Clinical Bacteriology and Mycology, Ku LeuvenBiomedical MRI unit/MoSAIC, Ku LeuvenImmunology and Transplantation, Laboratory of Clinical Bacteriology and Mycology, Ku LeuvenImmunology and Transplantation,Laboratory for Clinical Infectious and Inflammatory Disorders, Ku LeuvenBiomedical MRI unit/MoSAIC, Ku LeuvenBiomedical MRI unit/MoSAIC, Ku LeuvenImmunology and Transplantation, Laboratory of Virology and Chemotherapy (Rega Institute), Ku LeuvenUniversity of NottinghamRadboud University Medical CenterImmunology and Transplantation, Laboratory of Adaptive Immunity, Ku LeuvenKu LeuvenImmunology and Transplantation, Laboratory of Clinical Bacteriology and Mycology, Ku LeuvenImmunology and Transplantation,Laboratory for Clinical Infectious and Inflammatory Disorders, Ku LeuvenBiomedical MRI unit/MoSAIC, Ku LeuvenInvasive pulmonary aspergillosis (IPA) is a life-threatening fungal infection occurring mainly in immunocompromised patients. We recently identified IPA as an emerging co-infection with high mortality in critically ill, but otherwise immunocompetent influenza patients. The neuraminidase inhibitor oseltamivir is the current standard-of-care treatment in hospitalized influenza patients; however, its efficacy in influenza-associated pulmonary aspergillosis (IAPA) is not known. Therefore, we have established an imaging-supported double-hit mouse model to investigate the therapeutic effect of oseltamivir on the development of IAPA. Immunocompetent mice received intranasal instillation influenza A or PBS followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Oseltamivir treatment or placebo was started at day 0, day 2, or day 4. Daily monitoring included micro-computed tomography and bioluminescence imaging of pneumonia and fungal burden. Non-invasive biomarkers were complemented with imaging, molecular, immunological, and pathological analysis. Influenza virus-infected immunocompetent mice developed proven airway IPA upon co-infection with Aspergillus fumigatus, whereas non-influenza-infected mice fully cleared Aspergillus, confirming influenza as a risk factor for developing IPA. Longitudinal micro-CT showed pulmonary lesions after influenza infection worsening after Aspergillus co-infection, congruent with bioluminescence imaging and histology confirming Aspergillus pneumonia. Early oseltamivir treatment prevented severe influenza pneumonia and mitigated the development of IPA and associated mortality. A time-dependent treatment effect was consistently observed with imaging, molecular, and pathological analyses. Hence, our findings underscore the importance of initiating oseltamivir as soon as possible, to suppress influenza infection and mitigate the risk of potentially lethal IAPA disease.http://dx.doi.org/10.1080/21505594.2021.1974327influenza-associated pulmonary aspergillosisoseltamivirmultimodal preclinical imaging-supported mouse modelaspergillus fumigatusinfluenza |
| spellingShingle | Laura Seldeslachts Lore Vanderbeke Astrid Fremau Agustin Reséndiz-Sharpe Cato Jacobs Bo Laeveren Tessa Ostyn Lieve Naesens Matthias Brock Frank L. Van De Veerdonk Stephanie Humblet-Baron Erik Verbeken Katrien Lagrou Joost Wauters Greetje Vande Velde Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model Virulence influenza-associated pulmonary aspergillosis oseltamivir multimodal preclinical imaging-supported mouse model aspergillus fumigatus influenza |
| title | Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model |
| title_full | Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model |
| title_fullStr | Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model |
| title_full_unstemmed | Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model |
| title_short | Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model |
| title_sort | early oseltamivir reduces risk for influenza associated aspergillosis in a double hit murine model |
| topic | influenza-associated pulmonary aspergillosis oseltamivir multimodal preclinical imaging-supported mouse model aspergillus fumigatus influenza |
| url | http://dx.doi.org/10.1080/21505594.2021.1974327 |
| work_keys_str_mv | AT lauraseldeslachts earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT lorevanderbeke earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT astridfremau earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT agustinresendizsharpe earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT catojacobs earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT bolaeveren earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT tessaostyn earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT lievenaesens earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT matthiasbrock earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT franklvandeveerdonk earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT stephaniehumbletbaron earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT erikverbeken earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT katrienlagrou earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT joostwauters earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel AT greetjevandevelde earlyoseltamivirreducesriskforinfluenzaassociatedaspergillosisinadoublehitmurinemodel |