Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza
| Autor: | Rachael Racine, Jesse L. Bonin, Sharon L. Salmon, Tarani Kanta Barman, Dennis W. Metzger, Danielle Califano |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
RNA viruses
Influenza Viruses Viral Diseases Disease medicine.disease_cause Pathology and Laboratory Medicine Biochemistry Neutralization Mice 0302 clinical medicine Medical Conditions Interferon Influenza A virus Medicine and Health Sciences Biology (General) 0303 health sciences Mice Inbred BALB C biology Coinfection Pneumococcus Animal Models Bacterial Pathogens medicine.anatomical_structure Infectious Diseases Experimental Organism Systems Medical Microbiology Superinfection Viral Pathogens Viruses Disease Susceptibility Pathogens medicine.drug Signal Transduction Research Article QH301-705.5 Immunology Mouse Models Research and Analysis Methods Microbiology Virus 03 medical and health sciences Model Organisms Orthomyxoviridae Infections Virology Genetics medicine Animals Humans Molecular Biology Microbial Pathogens 030304 developmental biology Bacteria Organisms Biology and Life Sciences Streptococcus Proteins Pneumonia Pneumococcal RC581-607 biology.organism_classification Influenza Mice Inbred C57BL Co-Infections Animal Studies Parasitology Interferons Immunologic diseases. Allergy 030215 immunology Respiratory tract Orthomyxoviruses |
| Zdroj: | PLoS Pathogens, Vol 17, Iss 3, p e1009405 (2021) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza. Author summary Bacterial co-infections represent a common and challenging clinical complication of influenza. Type-I and type-II interferon (IFN) pathways enhance susceptibility to influenza-pneumococcal co-infection, leading to increased lung pathology and mortality. However, the comparative importance of type-I versus type-II IFN remains unclear. We have used two novel mouse models of co-infection in which pneumococci were inoculated into the upper respiratory tract followed two days later by influenza virus infection. Virus co-infection caused IFN-dependent inflammation that facilitated spreading of the colonizing bacteria into the lungs, followed by tissue damage and death. In this pneumococcal-influenza virus superinfection model, mice lacking both type-I and type-II IFN pathways demonstrated minimal lung pathology and increased survival compared to wild-type mice and mice deficient in only one pathway. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to superinfected wild-type mice. The most effective treatment regimen involved neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of the type-II IFN pathway. These results provide new insights into potential host-directed therapy for management of bacterial-viral superinfections. |
| Databáze: | OpenAIRE |
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