title: MicroRNA-155 is required for clearance of Streptococcus pneumoniae from the nasopharynx.
abstract: Pneumonia caused by Streptococcus pneumoniae is a major cause of death and an economic burden worldwide. S. pneumoniae is an intermittent colonizer of the human upper respiratory tract, and the ability to control asymptomatic colonization determines the likelihood of developing invasive disease. Recognition of S. pneumoniae by resident macrophages via Toll-like receptor 2 (TLR-2) and the macrophage receptor with collagenous structure (MARCO) and the presence of interleukin-17 (IL-17)-secreting CD4(+) T cells are required for macrophage recruitment and bacterial clearance. Despite the fact that the primary cellular effectors needed for bacterial clearance have been identified, much of the underlying regulatory mechanisms are unknown. Herein, we demonstrate that the small, noncoding RNA microRNA-155 (mir-155) is critical for the effective clearance of S. pneumoniae. Our studies show that mir-155-deficient mice maintain the ability to prevent acute invasive pneumococcal infection but have significantly higher bacterial burdens following colonization, independently of macrophage recognition by TLR-2, MARCO expression, or bactericidal capacity. The observed defects in bacterial clearance parallel reduced IL-17A and gamma interferon CD4(+) T-cell responses in vivo, lower IL-17A mRNA levels in the nasopharynx, and a reduced capacity to induce Th17 cell polarization. Given that knockout mice are also limited in the capacity to generate high-titer S. pneumoniae-specific antibodies, we conclude that mir-155 is a critical mediator of the cellular effectors needed to clear primary and secondary S. pneumoniae colonizations.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Chris P
authors.identifier: http://orcid.org/0000-0001-6190-2655
authors.initials: CP
authors.lastname: Verschoor
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Dorrington
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Novakowski
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Kaiser
authors.affiliation: Division of Respirology, Department of Medicine, St. Joseph's Healthcare and McMaster University, Hamilton, Ontario, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Radford
authors.affiliation: Division of Respirology, Department of Medicine, St. Joseph's Healthcare and McMaster University, Hamilton, Ontario, Canada.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Nair
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Varun
authors.initials: V
authors.lastname: Anipindi
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Charu
authors.initials: C
authors.lastname: Kaushic
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Surette
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada bowdish@mcmaster.ca.
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
mesh_terms: D000818:Animals; D002353:Carrier State; D005786:Gene Expression Regulation / Q000276:immunology; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009305:Nasopharynx / Q000276:immunology / Q000382:microbiology*; D010587:Phagocytosis; D013296:Streptococcus pneumoniae / Q000502:physiology*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse