期刊
EMBO REPORTS
卷 16, 期 9, 页码 1203-1218出版社
WILEY
DOI: 10.15252/embr.201540473
关键词
C-C-chemokine receptor type (CCR) 2; influenza; neutrophil; Streptococcus pneumoniae; TNF-related apoptosis-inducing ligand (TRAIL)
资金
- Francis Crick Institute from Cancer Research UK
- UK Medical Research Council
- Wellcome Trust
- MRC [U117597139, MC_UP_1202/13]
- MRC [MC_U117597139, MC_UP_1202/13] Funding Source: UKRI
- Medical Research Council [MC_U117597139, MC_UP_1202/13] Funding Source: researchfish
- The Francis Crick Institute [10129, 10206] Funding Source: researchfish
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-alpha 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-alpha and neutrophil responses help control subsequent bacterial outgrowth. We thus identify novel determinants of protection versus pathology in influenza-Streptococcus pneumoniae coinfection.
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