title: Inactivated influenza vaccine adjuvanted with bacterium-like particles induce systemic and mucosal influenza A virus specific T-cell and B-cell responses after nasal administration in a TLR2 dependent fashion.
abstract: BACKGROUND
  Nasal vaccination is considered to be a promising alternative for parenteral vaccination against influenza virus as it is non-invasive and offers the opportunity to elicit strong antigen-specific responses both systemic and locally at the port of entry of the pathogen. Previous studies showed that non-living bacterium-like particles (BLPs) from the food-grade bacterium Lactococcus lactis are effective stimulators of local and systemic immune responses when administered intranasally. Moreover, in vitro, BLPs specifically interact with human Toll-like receptor 2 (TLR2), suggestive of a role for TLR2 dependent immune activation by BLPs.
  
  
  METHODS
  In the present study, we examined the role of TLR2 in vivo in immune activation after nasal administration of BLP mixed with split influenza vaccine (BLP-SV) of influenza A virus (IAV) using TLR2 knockout mice.
  
  
  RESULTS
  The systemic Th1 cell and subsequent B-cell responses induced after intranasal BLP-SV vaccination depended on the interaction of BLPs with TLR2. Notably, the BLP-SV-induced class switch to IgG2c depended on the interaction of BLP with TLR2. Local induced IAV-specific Th1 cell responses and the mucosal B-cell responses also depended on interaction of BLP with TLR2. Strongly reduced SIgA levels were observed in TLR2 knockout mice both in the nasal and vaginal lavages. In addition, detailed analysis of the T-cell response revealed that nasal BLP-SV vaccination promoted Th1/Th17 immune responses that coincided with increased IAV-specific IgG2c antibody production.
  
  
  CONCLUSIONS
  Altogether these results indicate that nasal BLP-SV vaccination induces IAV-specific T-cell and B-cell responses, both systemically and at the site of virus entry in a TLR2-dependent manner.
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, NL-3584 CL Utrecht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Keijzer
authors.affiliation: Mucosis BV, L.J. Zielstraweg 1, NL-9713 GX Groningen, The Netherlands.
authors.forename: B J
authors.initials: BJ
authors.lastname: Haijema
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Meijerhof
authors.affiliation: Mucosis BV, L.J. Zielstraweg 1, NL-9713 GX Groningen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Voorn
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Haan
authors.affiliation: Mucosis BV, L.J. Zielstraweg 1, NL-9713 GX Groningen, The Netherlands. Electronic address: leenhouts@mucosis.com.
authors.forename: K
authors.initials: K
authors.lastname: Leenhouts
authors.affiliation: Mucosis BV, L.J. Zielstraweg 1, NL-9713 GX Groningen, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: van Roosmalen
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, NL-3584 CL Utrecht, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: van Eden
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, NL-3584 CL Utrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Broere
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D018928:Immunity, Mucosal; D007071:Immunoglobulin A, Secretory / Q000276:immunology; D007074:Immunoglobulin G / Q000145:classification / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D007252:Influenza Vaccines / Q000276:immunology*; D013294:Lactococcus lactis / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D018417:Th1 Cells / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; D007252:Influenza Vaccines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D015164:Vaccines, Inactivated
keywords: Bacterium-like particles (BLP); Humoral immunity; Influenza A virus; Nasal vaccination; T-cell responses; Toll-like receptor 2 (TLR2)