TY - JOUR
T1 - NOD2/RIG-I Activating Inarigivir Adjuvant Enhances the Efficacy of BCG Vaccine Against Tuberculosis in Mice
AU - Khan, Arshad
AU - Singh, Vipul K.
AU - Mishra, Abhishek
AU - Soudani, Emily
AU - Bakhru, Pearl
AU - Singh, Christopher R.
AU - Zhang, Dekai
AU - Canaday, David H.
AU - Sheri, Anjaneyulu
AU - Padmanabhan, Seetharamaiyer
AU - Challa, Sreerupa
AU - Iyer, Radhakrishnan P.
AU - Jagannath, Chinnaswamy
N1 - Copyright © 2020 Khan, Singh, Mishra, Soudani, Bakhru, Singh, Zhang, Canaday, Sheri, Padmanabhan, Challa, Iyer and Jagannath.
PY - 2020/12/7
Y1 - 2020/12/7
N2 - 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-β, and Caspase-1 dependent IL-1β 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.
AB - 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-β, and Caspase-1 dependent IL-1β 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.
KW - BCG vaccine
KW - NOD2
KW - RIG-I
KW - adjuvants
KW - antigen presentation
KW - inarigivir
KW - inflammasome
KW - tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85098053356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098053356&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.592333
DO - 10.3389/fimmu.2020.592333
M3 - Article
C2 - 33365029
SN - 1664-3224
VL - 11
SP - 3134
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 592333
ER -