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1.
Front Immunol ; 11: 592333, 2020.
Article in English | MEDLINE | ID: mdl-33365029

ABSTRACT

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) kills about 1.5 million people each year and the widely used Bacille Calmette-Guérin (BCG) vaccine provides a partial protection against TB in children and adults. Because BCG vaccine evades lysosomal fusion in antigen presenting cells (APCs), leading to an inefficient production of peptides and antigen presentation required to activate CD4 T cells, we sought to boost its efficacy using novel agonists of RIG-I and NOD2 as adjuvants. We recently reported that the dinucleotide SB 9200 (Inarigivir) derived from our small molecule nucleic acid hybrid (SMNH)® platform, activated RIG-I and NOD2 receptors and exhibited a broad-spectrum antiviral activity against hepatitis B and C, Norovirus, RSV, influenza and parainfluenza. Inarigivir increased the ability of BCG-infected mouse APCs to secrete elevated levels of IL-12, TNF-α, and IFN-ß, and Caspase-1 dependent IL-1ß cytokine. Inarigivir also increased the ability of macrophages to kill MTB in a Caspase-1-, and autophagy-dependent manner. Furthermore, Inarigivir led to a Capsase-1 and NOD2- dependent increase in the ability of BCG-infected APCs to present an Ag85B-p25 epitope to CD4 T cells in vitro. Consistent with an increase in immunogenicity of adjuvant treated APCs, the Inarigivir-BCG vaccine combination induced robust protection against tuberculosis in a mouse model of MTB infection, decreasing the lung burden of MTB by 1-log10 more than that afforded by BCG vaccine alone. The Inarigivir-BCG combination was also more efficacious than a muramyl-dipeptide-BCG vaccine combination against tuberculosis in mice, generating better memory T cell responses supporting its novel adjuvant potential for the BCG vaccine.


Subject(s)
Adjuvants, Immunologic , BCG Vaccine/immunology , Mycobacterium tuberculosis/immunology , Nod2 Signaling Adaptor Protein/metabolism , Receptors, Cell Surface/metabolism , Tuberculosis/metabolism , Tuberculosis/prevention & control , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , Antigen Presentation/immunology , Antigens, Bacterial/immunology , Chromobox Protein Homolog 5 , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Immunologic Memory , Immunomodulation , Macrophages/immunology , Macrophages/metabolism , Mice , Mycobacterium tuberculosis/drug effects , Protein Binding , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Tuberculosis/genetics
2.
NPJ Vaccines ; 4: 34, 2019.
Article in English | MEDLINE | ID: mdl-31396406

ABSTRACT

Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis due to M. tuberculosis (Mtb), which kills millions of people each year. BCG variably protects children, but not adults against tuberculosis. BCG evades phagosome maturation, autophagy, and reduces MHC-II expression of antigen-presenting cells (APCs) affecting T-cell activation. To bypass these defects, an autophagy-inducing, TLR-2 activating C5 peptide from Mtb-derived CFP-10 protein was overexpressed in BCG in combination with Ag85B. Recombinant BCG85C5 induced a robust MHC-II-dependent antigen presentation to CD4 T cells in vitro, and elicited stronger TH1 cytokines (IL-12, IL-1ß, and TNFα) from APCs of C57Bl/6 mice increasing phosphorylation of p38MAPK and ERK. BCG85C5 also enhanced MHC-II surface expression of MΦs by inhibiting MARCH1 ubiquitin ligase that degrades MHC-II. BCG85C5 infected APCs from MyD88 or TLR-2 knockout mice showed decreased antigen presentation. Furthermore, BCG85C5 induced LC3-dependent autophagy in macrophages increasing antigen presentation. Consistent with in vitro effects, BCG85C5 markedly expanded both effector and central memory T cells in C57Bl/6 mice protecting them against both primary aerosol infection with Mtb and reinfection, but was less effective among TLR-2 knockout mice. Thus, BCG85C5 induces stronger and longer lasting immunity, and is better than BCG against tuberculosis of mice.

3.
Cell Immunol ; 287(1): 53-61, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24384074

ABSTRACT

Tuberculosis is a major cause of death in mankind and BCG vaccine protects against childhood but not adult tuberculosis. BCG avoids lysosomal fusion in macrophages decreasing peptides required for activating CD4 T cells and Th1 immunity while suppressing the expression of MHC-II by antigen presenting cells (APCs). An in vitro model of antigen presentation showed that ligands for TLR-9, 7, 4 and 1/2 increased the ability of APCs to present antigen-85B of BCG to CD4 T cells, which correlated with an increase in MHC-II expression. TLR-activation led to a down-regulation of MARCH1 ubiquitin ligase which prevents the degradation of MHC-II and decreased IL-10 also contributed to an increase in MHC-II. TLR-activation induced up-regulation of MHC-II was inhibited by the blockade of IRAK, NF-kB, and MAPKs. TLR-7 and TLR-9 ligands had the most effective adjuvant like effect on MHC-II of APCs which allowed BCG vaccine mediated activation of CD4 T cells.


Subject(s)
BCG Vaccine , CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Macrophages/immunology , Mycobacterium tuberculosis/immunology , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 9/metabolism , Tuberculosis/immunology , Acyltransferases/immunology , Animals , Antigen Presentation/genetics , Antigens, Bacterial/immunology , Antigens, Bacterial/pharmacology , CD4-Positive T-Lymphocytes/microbiology , Cells, Cultured , Dendritic Cells/microbiology , Female , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/metabolism , Humans , Interleukin-10/genetics , Interleukin-10/metabolism , Lipopolysaccharides/pharmacology , MAP Kinase Signaling System , Macrophages/microbiology , Male , Mice , Mice, Inbred C57BL , RNA, Small Interfering/genetics , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
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