title: Viral and bacterial co-infection in severe pneumonia triggers innate immune responses and specifically enhances IP-10: a translational study.
abstract: Mixed viral and bacterial infections are widely described in community-acquired pneumonia; however, the clinical implications of co-infection on the associated immunopathology remain poorly studied. In this study, microRNA, mRNA and cytokine/chemokine secretion profiling were investigated for human monocyte-derived macrophages infected in-vitro with Influenza virus A/H1N1 and/or Streptococcus pneumoniae. We observed that the in-vitro co-infection synergistically increased interferon-γ-induced protein-10 (CXCL10, IP-10) expression compared to the singly-infected cells conditions. We demonstrated that endogenous miRNA-200a-3p, whose expression was synergistically induced following co-infection, indirectly regulates CXCL10 expression by targeting suppressor of cytokine signaling-6 (SOCS-6), a well-known regulator of the JAK-STAT signaling pathway. Additionally, in a subsequent clinical pilot study, immunomodulators levels were evaluated in samples from 74 children (≤5 years-old) hospitalized with viral and/or bacterial community-acquired pneumonia. Clinically, among the 74 cases of pneumonia, patients with identified mixed-detection had significantly higher (3.6-fold) serum IP-10 levels than those with a single detection (P = 0.03), and were significantly associated with severe pneumonia (P < 0.01). This study demonstrates that viral and bacterial co-infection modulates the JAK-STAT signaling pathway and leads to exacerbated IP-10 expression, which could play a major role in the pathogenesis of pneumonia.
authors.affiliation: Laboratoire des Pathogènes Émergents, Fondation Mérieux - CIRI - Inserm U1111, Lyon, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Laboratoire des Pathogènes Émergents, Fondation Mérieux - CIRI - Inserm U1111, Lyon, France.
authors.forename: Daniela
authors.initials: D
authors.lastname: Machado
authors.affiliation: Virologie et Pathologie Humaine VirPath, CIRI - UCBL1 - Inserm U1111 - CNRS UMR 5308 - ENS de Lyon, Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Terrier
authors.affiliation: Laboratoire des Pathogènes Émergents, Fondation Mérieux - CIRI - Inserm U1111, Lyon, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Pouzol
authors.affiliation: Laboratoire des Pathogènes Émergents, Fondation Mérieux - CIRI - Inserm U1111, Lyon, France.
authors.forename: Mélina
authors.initials: M
authors.lastname: Messaoudi
authors.affiliation: Hospital General Pediátrico Niños de Acosta Ñu, Ministerio de Salud Pública y Bienestar Social, Paraguay.
authors.forename: Wilma
authors.initials: W
authors.lastname: Basualdo
authors.affiliation: Departamento de Biología Molecular y Biotecnologia, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Paraguay.
authors.forename: Emilio E
authors.initials: EE
authors.lastname: Espínola
authors.affiliation: Departamento de Biología Molecular y Biotecnologia, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Paraguay.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Guillen
authors.affiliation: Virologie et Pathologie Humaine VirPath, CIRI - UCBL1 - Inserm U1111 - CNRS UMR 5308 - ENS de Lyon, Lyon, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rosa-Calatrava
authors.affiliation: Laboratoire des Pathogènes Émergents, Fondation Mérieux - CIRI - Inserm U1111, Lyon, France.
authors.forename: Valentina
authors.initials: V
authors.lastname: Picot
authors.affiliation: Infection Control and Epidemiology Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bénet
authors.affiliation: Laboratoire des Pathogènes Émergents, Fondation Mérieux - CIRI - Inserm U1111, Lyon, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Endtz
authors.affiliation: Departamento de Biología Molecular y Biotecnologia, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Paraguay.
authors.forename: Graciela
authors.initials: G
authors.lastname: Russomando
authors.affiliation: Laboratoire des Pathogènes Émergents, Fondation Mérieux - CIRI - Inserm U1111, Lyon, France.
authors.forename: Gláucia
authors.initials: G
authors.lastname: Paranhos-Baccalà
mesh_terms: D000328:Adult; D000368:Aged; D001424:Bacterial Infections / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D001483:Base Sequence; D054357:Chemokine CXCL10 / Q000378:metabolism*; D060085:Coinfection / Q000276:immunology / Q000382:microbiology* / Q000821:virology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007223:Infant; D053118:Influenza A Virus, H1N1 Subtype; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013296:Streptococcus pneumoniae; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D057170:Translational Research, Biomedical; D014777:Virus Diseases / Q000276:immunology*; D055815:Young Adult
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D035683:MicroRNAs; D012333:RNA, Messenger; C473085:SOCS6 protein, human; D050826:Suppressor of Cytokine Signaling Proteins