Pulmonary mucosal immunity mediated through CpG provides adequate protection against pulmonary Mycobacterium tuberculosis infection in the mouse model. A role for type I interferon

Tuberculosis (Edinb). 2020 Jul:123:101949. doi: 10.1016/j.tube.2020.101949. Epub 2020 Jun 6.

Abstract

Toll-Like Receptor (TLR) 9 stimulation is required for induction of potent immune responses against pathogen invasion. The use of unmethylated CpG as adjuvants in vaccines provides an excellent means of stimulating adaptive immunity. Our data demonstrate that CpG-C provided prolonged immune responses in the mouse model of tuberculosis when formulated with liposomes and the Mycobacterium tuberculosis antigen ESAT-6. A reduction in the mycobacterial burden was best achieved when administered as an intranasal vaccine and was dependent on type I interferon (IFN). There was a significant difference between CpG-C inoculated wild type and IFN-αR1-/- mice, indicating that type I IFN plays a role in the immune response following CpG-C inoculation. Further analysis showed that early NK cell presence was not an absolute requirement, although elevated IFN-γ levels were detected in the lungs of mice within 48 h. The reduction in mycobacterial burden was MyD88-independent as CpG-C inoculated MyD88-/- mice showed comparable mycobacterial burdens to wild type mice with no detriment due to the lack of MyD88. Together our data show that pulmonary stimulation of TLR9 bearing antigen presenting cells resulted in the induction of protective immunity against M. tuberculosis infection that was dependent on type I IFN signaling.

Keywords: CpG-C; Pulmonary immunity; TLR9; Tuberculosis; Type I IFN; Vaccine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Adjuvants, Immunologic / adverse effects
  • Administration, Intranasal
  • Animals
  • Antigens, Bacterial / administration & dosage*
  • Bacterial Proteins / administration & dosage*
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Host-Pathogen Interactions
  • Immunity, Mucosal / drug effects*
  • Interferon-gamma / metabolism
  • Lung / drug effects*
  • Lung / immunology
  • Lung / metabolism
  • Lung / microbiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / pathogenicity
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Nasal Sprays
  • Oligodeoxyribonucleotides / administration & dosage*
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / microbiology
  • Signal Transduction
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / metabolism
  • Tuberculosis Vaccines / administration & dosage*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / metabolism
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / prevention & control*

Substances

  • Adjuvants, Immunologic
  • Antigens, Bacterial
  • Bacterial Proteins
  • CpG ODN 2216
  • CpG ODN 2395
  • ESAT-6 protein, Mycobacterium tuberculosis
  • IFNG protein, mouse
  • Ifnar1 protein, mouse
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Nasal Sprays
  • Oligodeoxyribonucleotides
  • ProMune
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Tuberculosis Vaccines
  • Receptor, Interferon alpha-beta
  • Interferon-gamma