Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis.
Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-02-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011840&type=printable |
| _version_ | 1827346000237297664 |
|---|---|
| author | Yu Zhang Jiuyang Xu Margot Miranda-Katz Jorna Sojati Sharon J Tollefson Michelle L Manni John F Alcorn Saumendra N Sarkar John V Williams |
| author_facet | Yu Zhang Jiuyang Xu Margot Miranda-Katz Jorna Sojati Sharon J Tollefson Michelle L Manni John F Alcorn Saumendra N Sarkar John V Williams |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV. In this study, we isolated and characterized a panel of low passage HMPV clinical isolates representing all four genetic subgroups. The clinical isolates exhibited lower levels of in vitro replication compared to a lab-adapted strain. We compared disease phenotypes using a well-established mouse model. Several virulent isolates caused severe weight loss, lung pathology, airway dysfunction, and fatal disease in mice, which was confirmed in three inbred mouse strains. Disease severity did not correlate with lung viral titer, as virulent strains exhibited restricted replication in the lower airway. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production and neutrophil influx; however, depletion of neutrophils or genetic ablation of inflammasome components did not reverse disease. Virulent clinical isolates induced markedly increased type I and type III interferon (IFN) secretion in vitro and in vivo. STAT1/2-deficient mice lacking both type I and type III IFN signaling showed reduced disease severity and increased lung viral replication. Inhibition of type I IFN signaling using a blocking antibody or genetic ablation of the type I IFN receptor reduced pathology with minimal effect on viral replication. Conversely, blockade of type III IFN signaling with a neutralizing antibody or genetic ablation of the IFN-lambda receptor had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV pathogenesis and immunity. |
| first_indexed | 2024-03-07T23:21:49Z |
| format | Article |
| id | doaj.art-6c53634f17784f9eb5425badd0b949ab |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-07T23:21:49Z |
| publishDate | 2024-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-6c53634f17784f9eb5425badd0b949ab2024-02-21T05:31:32ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-02-01202e101184010.1371/journal.ppat.1011840Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis.Yu ZhangJiuyang XuMargot Miranda-KatzJorna SojatiSharon J TollefsonMichelle L ManniJohn F AlcornSaumendra N SarkarJohn V WilliamsHuman metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV. In this study, we isolated and characterized a panel of low passage HMPV clinical isolates representing all four genetic subgroups. The clinical isolates exhibited lower levels of in vitro replication compared to a lab-adapted strain. We compared disease phenotypes using a well-established mouse model. Several virulent isolates caused severe weight loss, lung pathology, airway dysfunction, and fatal disease in mice, which was confirmed in three inbred mouse strains. Disease severity did not correlate with lung viral titer, as virulent strains exhibited restricted replication in the lower airway. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production and neutrophil influx; however, depletion of neutrophils or genetic ablation of inflammasome components did not reverse disease. Virulent clinical isolates induced markedly increased type I and type III interferon (IFN) secretion in vitro and in vivo. STAT1/2-deficient mice lacking both type I and type III IFN signaling showed reduced disease severity and increased lung viral replication. Inhibition of type I IFN signaling using a blocking antibody or genetic ablation of the type I IFN receptor reduced pathology with minimal effect on viral replication. Conversely, blockade of type III IFN signaling with a neutralizing antibody or genetic ablation of the IFN-lambda receptor had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV pathogenesis and immunity.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011840&type=printable |
| spellingShingle | Yu Zhang Jiuyang Xu Margot Miranda-Katz Jorna Sojati Sharon J Tollefson Michelle L Manni John F Alcorn Saumendra N Sarkar John V Williams Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis. PLoS Pathogens |
| title | Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis. |
| title_full | Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis. |
| title_fullStr | Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis. |
| title_full_unstemmed | Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis. |
| title_short | Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis. |
| title_sort | distinct roles for type i and type iii interferons in virulent human metapneumovirus pathogenesis |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011840&type=printable |
| work_keys_str_mv | AT yuzhang distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT jiuyangxu distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT margotmirandakatz distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT jornasojati distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT sharonjtollefson distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT michellelmanni distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT johnfalcorn distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT saumendransarkar distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis AT johnvwilliams distinctrolesfortypeiandtypeiiiinterferonsinvirulenthumanmetapneumoviruspathogenesis |