embr.201540473.pdf (963.26 kB)
TRAIL+ monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection
journal contributionposted on 2020-07-21, 10:51 authored by Gregory T Ellis, Sophia Davidson, Stefania Crotta, Nora Branzk, Venizelos Papayannopoulos, Andreas Wack
Streptococcus pneumoniae coinfection is a major cause of influenza-associated mortality; however, the mechanisms underlying pathogenesis or protection remain unclear. Using a clinically relevant mouse model, we identify immune-mediated damage early during coinfection as a new mechanism causing susceptibility. Coinfected CCR2(-/-) mice lacking monocytes and monocyte-derived cells control bacterial invasion better, show reduced epithelial damage and are overall more resistant than wild-type controls. In influenza-infected wild-type lungs, monocytes and monocyte-derived cells are the major cell populations expressing the apoptosis-inducing ligand TRAIL. Accordingly, anti-TRAIL treatment reduces bacterial load and protects against coinfection if administered during viral infection, but not following bacterial exposure. Post-influenza bacterial outgrowth induces a strong proinflammatory cytokine response and massive inflammatory cell infiltrate. Depletion of neutrophils or blockade of TNF-α facilitate bacterial outgrowth, leading to increased mortality, demonstrating that these factors aid bacterial control. We conclude that inflammatory monocytes recruited early, during the viral phase of coinfection, induce TRAIL-mediated lung damage, which facilitates bacterial invasion, while TNF-α and neutrophil responses help control subsequent bacterial outgrowth. We thus identify novel determinants of protection versus pathology in influenza-Streptococcus pneumoniae coinfection.
C‐C‐chemokine receptor type (CCR) 2Streptococcus pneumoniaeTNF‐related apoptosis‐inducing ligand (TRAIL)influenzaneutrophilAnimalsCoinfectionCytokinesDisease Models, AnimalDisease SusceptibilityHumansInfluenza A Virus, H3N2 SubtypeLungMiceMice, Inbred C57BLMonocytesNeutrophilsOrthomyxoviridae InfectionsPneumococcal InfectionsReceptors, CCR2TNF-Related Apoptosis-Inducing LigandTumor Necrosis Factor-alphaWack U117597139Papayannopoulos MC_UP_1202/13BRF-ackHP-ackFC-ackLM-ackDevelopmental Biology0601 Biochemistry and Cell Biology