title: Single immunoglobulin interleukin-1 receptor-related molecule impairs host defense during pneumonia and sepsis caused by Streptococcus pneumoniae.
abstract: Streptococcus pneumoniae is a common cause of pneumonia and sepsis. Toll-like receptors (TLRs) play a pivotal role in the host defense against infection. In this study, we sought to determine the role of single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR a.k.a. TIR8), a negative regulator of TLR signaling, in pneumococcal pneumonia and sepsis. Wild-type and SIGIRR-deficient (sigirr-/-) mice were infected intranasally (to induce pneumonia) or intravenously (to induce primary sepsis) with S. pneumoniae and euthanized after 6, 24, or 48 h for analyses. Additionally, survival studies were performed. sigirr-/- mice showed delayed mortality during lethal pneumococcal pneumonia. Accordingly, sigirr-/- mice displayed lower bacterial loads in lungs and less dissemination of the infection 24 h after the induction of pneumonia. SIGIRR deficiency was associated with increased interstitial and perivascular inflammation in lung tissue early after infection, with no impact on neutrophil recruitment or cytokine production. sigirr-/- mice also demonstrated reduced bacterial burdens at multiple body sites during S. pneumoniae sepsis. sigirr-/- alveolar macrophages and neutrophils exhibited an increased capacity to phagocytose viable pneumococci. These results suggest that SIGIRR impairs the antibacterial host defense during pneumonia and sepsis caused by S. pneumoniae.
authors.affiliation: Center of Experimental and Molecular Medicine, Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Blok
authors.forename: Miriam H P
authors.initials: MH
authors.lastname: van Lieshout
authors.forename: Arie J
authors.initials: AJ
authors.lastname: Hoogendijk
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Onno J
authors.initials: OJ
authors.lastname: de Boer
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Cornelis
authors.initials: C
authors.lastname: van't Veer
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000235:genetics; D002478:Cells, Cultured; D008168:Lung / Q000382:microbiology / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D010587:Phagocytosis / Q000235:genetics; D018410:Pneumonia, Bacterial / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D013290:Streptococcal Infections / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C484529:SIGIRR protein, mouse