Retinoic acid pre-treatment down regulates V. cholerae outer membrane vesicles induced acute inflammation and enhances mucosal immunity

Vaccine. 2017 Jun 16;35(28):3534-3547. doi: 10.1016/j.vaccine.2017.05.036. Epub 2017 May 22.

Abstract

Bacterial outer membrane vesicles have been extensively investigated and considered as a next generation vaccine. Recently, we have demonstrated that the cholera pentavalent outer membrane vesicles (CPMVs) immunogen induced adaptive immunity and had a strong protective efficacy against the circulating V. cholerae strains in a mouse model. In this present study, we are mainly focusing on reducing outer membrane vesicle (OMV) -mediated toxicity without altering its antigenic property. Therefore, we have selected All-trans Retinoic Acid (ATRA), active metabolites of vitamin A, which have both anti-inflammatory and mucosal adjuvant properties. Pre-treatment of ATRA significantly reduced CPMVs induced TLR2 mediated pro-inflammatory responses in vitro and in vivo. Furthermore, we also found ATRA pre-treatment significantly induced mucosal immune response and protective efficacy after two doses of oral immunization with CPMVs (75µg). This study can help to reduce OMV based vaccine toxicity and induce better protective immunity where children and men suffered from malnutrition mainly in developing countries.

Keywords: ATRA; CPMVs; Cholera; OMVs; TLR2.

MeSH terms

  • Administration, Oral
  • Animals
  • Animals, Newborn
  • Antibodies, Bacterial / blood
  • Bacterial Outer Membrane Proteins / immunology*
  • Bacterial Outer Membrane Proteins / toxicity
  • Cholera / immunology
  • Cholera / prevention & control
  • Cholera Vaccines / administration & dosage
  • Cholera Vaccines / immunology*
  • Cholera Vaccines / toxicity
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Female
  • Immunity, Mucosal*
  • Immunogenicity, Vaccine
  • Immunoglobulin G / blood
  • Inflammation / prevention & control*
  • Mice
  • Mice, Inbred BALB C
  • Toll-Like Receptor 2 / immunology
  • Tretinoin / administration & dosage*
  • Tretinoin / immunology
  • Tretinoin / pharmacology
  • Vibrio cholerae / immunology*

Substances

  • Antibodies, Bacterial
  • Bacterial Outer Membrane Proteins
  • Cholera Vaccines
  • Cytokines
  • Immunoglobulin G
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Tretinoin