title: Novel Strategy To Protect against Influenza Virus-Induced Pneumococcal Disease without Interfering with Commensal Colonization.
abstract: Streptococcus pneumoniae commonly inhabits the nasopharynx as a member of the commensal biofilm. Infection with respiratory viruses, such as influenza A virus, induces commensal S. pneumoniae to disseminate beyond the nasopharynx and to elicit severe infections of the middle ears, lungs, and blood that are associated with high rates of morbidity and mortality. Current preventive strategies, including the polysaccharide conjugate vaccines, aim to eliminate asymptomatic carriage with vaccine-type pneumococci. However, this has resulted in serotype replacement with, so far, less fit pneumococcal strains, which has changed the nasopharyngeal flora, opening the niche for entry of other virulent pathogens (e.g., Streptococcus pyogenes, Staphylococcus aureus, and potentially Haemophilus influenzae). The long-term effects of these changes are unknown. Here, we present an attractive, alternative preventive approach where we subvert virus-induced pneumococcal disease without interfering with commensal colonization, thus specifically targeting disease-causing organisms. In that regard, pneumococcal surface protein A (PspA), a major surface protein of pneumococci, is a promising vaccine target. Intradermal (i.d.) immunization of mice with recombinant PspA in combination with LT-IIb(T13I), a novel i.d. adjuvant of the type II heat-labile enterotoxin family, elicited strong systemic PspA-specific IgG responses without inducing mucosal anti-PspA IgA responses. This response protected mice from otitis media, pneumonia, and septicemia and averted the cytokine storm associated with septic infection but had no effect on asymptomatic colonization. Our results firmly demonstrated that this immunization strategy against virally induced pneumococcal disease can be conferred without disturbing the desirable preexisting commensal colonization of the nasopharynx.
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Greene
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Marks
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Hu
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Reddinger
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: Lorrie
authors.initials: L
authors.lastname: Mandell
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: Hazeline
authors.initials: H
authors.lastname: Roche-Hakansson
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: King-Lyons
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA connell@buffalo.edu anders_p.hakansson@med.lu.se.|The Witebsky Center for Microbial Pathogenesis and Immunology, The University at Buffalo, Buffalo, New York, USA.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Connell
authors.affiliation: The Department of Microbiology and Immunology, The University at Buffalo, Buffalo, New York, USA connell@buffalo.edu anders_p.hakansson@med.lu.se.|The Witebsky Center for Microbial Pathogenesis and Immunology, The University at Buffalo, Buffalo, New York, USA.|New York State Center of Excellence in Bioinformatics and Life Sciences, The University at Buffalo, Buffalo, New York, USA.|Division of Experimental Infection Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: Anders P
authors.identifier: http://orcid.org/0000-0002-2834-6009
authors.initials: AP
authors.lastname: Hakansson
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics; D000281:Administration, Intranasal; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D004768:Enterotoxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D056724:Immunity, Humoral / Q000187:drug effects; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D007271:Injections, Intradermal; D051379:Mice; D008807:Mice, Inbred BALB C; D009305:Nasopharynx / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D022242:Pneumococcal Vaccines / Q000008:administration & dosage*; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D013559:Symbiosis / Q000187:drug effects; D018074:Vaccines, Conjugate
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D011994:Recombinant Proteins; D018074:Vaccines, Conjugate; C051592:pneumococcal surface protein A; C027538:heat-labile enterotoxin, E coli