TRAIL+ monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection.
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.
Mill Hill Laboratory, Francis Crick Institute, London, UK.
Gregory T
GT
Ellis
Mill Hill Laboratory, Francis Crick Institute, London, UK.
Sophia
S
Davidson
Mill Hill Laboratory, Francis Crick Institute, London, UK.
Stefania
S
Crotta
Mill Hill Laboratory, Francis Crick Institute, London, UK.
Nora
N
Branzk
Mill Hill Laboratory, Francis Crick Institute, London, UK.
Venizelos
V
Papayannopoulos
Mill Hill Laboratory, Francis Crick Institute, London, UK andreas.wack@crick.ac.uk.
Andreas
A
Wack
D000818:Animals; D060085:Coinfection / Q000276:immunology* / Q000503:physiopathology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology*; D011008:Pneumococcal Infections / Q000150:complications / Q000276:immunology*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
C515335:Ccr2 protein, mouse; D016207:Cytokines; D054390:Receptors, CCR2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha
C‐C‐chemokine receptor type (CCR) 2; Streptococcus pneumoniae; TNF‐related apoptosis‐inducing ligand (TRAIL); influenza; neutrophil