title: Pulmonary immunostimulation with MALP-2 in influenza virus-infected mice increases survival after pneumococcal superinfection.
abstract: Pulmonary infection with influenza virus is frequently complicated by bacterial superinfection, with Streptococcus pneumoniae being the most prevalent causal pathogen and hence often associated with high morbidity and mortality rates. Local immunosuppression due to pulmonary influenza virus infection has been identified as a major cause of the pathogenesis of secondary bacterial lung infection. Thus, specific local stimulation of the pulmonary innate immune system in subjects with influenza virus infection might improve the host defense against secondary bacterial pathogens. In the present study, we examined the effect of pulmonary immunostimulation with Toll-like receptor 2 (TLR-2)-stimulating macrophage-activating lipopeptide 2 (MALP-2) in influenza A virus (IAV)-infected mice on the course of subsequent pneumococcal superinfection. Female C57BL/6N mice infected with IAV were treated with MALP-2 on day 5 and challenged with S. pneumoniae on day 6. Intratracheal MALP-2 application increased proinflammatory cytokine and chemokine release and enhanced the recruitment of leukocytes, mainly neutrophils, into the alveolar space of IAV-infected mice, without detectable systemic side effects. Local pulmonary instillation of MALP-2 in IAV-infected mice 24 h before transnasal pneumococcal infection considerably reduced the bacterial number in the lung tissue without inducing exaggerated inflammation. The pulmonary viral load was not altered by MALP-2. Clinically, MALP-2 treatment of IAV-infected mice increased survival rates and reduced hypothermia and body weight loss after pneumococcal superinfection compared to those of untreated coinfected mice. In conclusion, local immunostimulation with MALP-2 in influenza virus-infected mice improved pulmonary bacterial elimination and increased survival after subsequent pneumococcal superinfection.
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Reppe
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Radünzel
authors.affiliation: Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Dietert
authors.affiliation: Institute of Anatomy and Cell Biology, Saarland University, Faculty of Medicine, Homburg/Saar, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.affiliation: Robert Koch Institute, Division of Influenza and Other Respiratory Viruses, Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.affiliation: Department of Genetics of Microorganisms, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Sven
authors.identifier: http://orcid.org/0000-0002-6382-6681
authors.initials: S
authors.lastname: Hammerschmidt
authors.affiliation: Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany martin.witzenrath@charite.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
mesh_terms: D000818:Animals; D060085:Coinfection; D005260:Female; D007035:Hypothermia / Q000517:prevention & control; D007113:Immunity, Innate; D007114:Immunization; D007155:Immunologic Factors / Q000494:pharmacology*; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity; D055666:Lipopeptides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology / Q000821:virology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity; D016019:Survival Analysis; D015431:Weight Loss / Q000187:drug effects
chemical_list: D007155:Immunologic Factors; D055666:Lipopeptides; C106335:macrophage stimulatory lipopeptide 2