title: Marked improvement of severe lung immunopathology by influenza-associated pneumococcal superinfection requires the control of both bacterial replication and host immune responses.
abstract: Bacterial superinfection and associated lung immunopathology are major contributors to hospitalizations and mortality after influenza. However, the underlying mechanisms and effective intervention strategies remain poorly defined. By using a model of influenza and pneumococcal superinfection, we found that dual-infected animals experienced rapid weight loss and succumbed to infection. Bacterial outgrowth, dysregulated cytokines, including keratinocyte-derived chemokine and macrophage inflammatory protein 2, and severe lung neutrophilia and immunopathology were linked to the poor clinical outcome. In vivo neutralization of highly induced macrophage inflammatory protein 2 did not affect clinical outcome, bacterial loads, or lung immunopathology. On the other hand, in vivo neutrophil depletion did not alter the clinical outcome and bacterial burden, although it moderately improved lung immunopathology. Treatment with a bacteriostatic antibiotic, azithromycin, alone significantly improved clinical outcome and bacterial clearance, but failed to reduce lung immunopathology. In comparison, treatment with a global inflammation inhibitor, dexamethasone, alone failed to alter clinical outcome, bacterial infection, and immunopathology, despite its moderate reducing effects on neutrophilic and cytokine responses. In contrast, combined treatment with both azithromycin and dexamethasone best improved clinical outcome, bacterial clearance, lung cellular and cytokine responses, and immunopathology. Our study suggests that marked improvement of clinical outcome and lung immunopathology caused by bacterial superinfection requires the control of both bacterial infection and aberrant host immune responses. Our findings hold implications in clinical management for influenza-associated bacterial superinfections.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Damjanovic
authors.forename: Rocky
authors.initials: R
authors.lastname: Lai
authors.forename: Mangalakumari
authors.initials: M
authors.lastname: Jeyanathan
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D054426:Chemokine CXCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004198:Disease Susceptibility / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000821:virology; D005260:Female; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D007109:Immunity / Q000187:drug effects / Q000276:immunology*; D007167:Immunotherapy; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D020556:Neutrophil Infiltration / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development*; D015163:Superinfection / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology / Q000821:virology*; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D054426:Chemokine CXCL2; D018925:Chemokines