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Fig. 2 | Cell & Bioscience

Fig. 2

From: Potential of helper-dependent Adenoviral vectors in CRISPR-cas9-mediated lung gene therapy

Fig. 2

Host immune responses to adenoviral vectors. (Left side) Innate immune responses. Innate immune responses to adenoviral vectors are triggered through the recognition of adenoviral pathogen-associated molecular patterns (PAMPs), including viral capsid proteins and viral nucleic acids, by pattern recognition receptors (PRRs). PPRs involved in recognition of adenoviral PAMPS include Toll-like receptors (TLRs), such as TLR4 which interacts with viral capsid proteins at the cell surface and TLR9 which recognizes viral DNA in endosomes, and cytosolic retinoic acid-inducible gene I (RIG-I) receptor. TLR4 triggers an intracellular signaling pathway mediated by proteins including myeloid differentiation primary response gene 88 (MyD88), TNF receptor-associated factor 6 (TRAF6), IL-1 receptor-associated kinase (IRAK). This activates nuclear factor-κB (NF-κB) through a kinase IKK (I-kB kinase) and interferon (IFN) regulatory factors, such as IRF3 and IRF7, resulting in expression of cytokines and chemokines, including type I IFNs. TLR9 recognizes viral dsDNA in the endosome converging the signal to the same pathway. RIG-I recognizes viral RNA 1 and 2 (VAI/II) transcribed by RNA polymerase III and channel the information to the same pathway through IKK. In addition, another class of PRRs, nucleotide-binding oligomerization domain-like receptors (NLRs), NOD2 and NALP3, recognizes dsDNA in the cytosol and activates the inflammasome leading to the upregulation of the same pathways. Finally, the cyclic GMP-AMP synthase/ stimulator of IFN genes (cGAS/STING) pathway can also recognize cytosolic viral DNA also leading to the upregulation of the same pathway. As HD-Ad does not contain viral coding sequences, it will not produce viral RNAs. (Right side) Adaptive immune responses. T cells recognize antigen presented on major histocompatibility complex (MHC) by antigen presenting cells (APCs), commonly dendritic cells. CD4 + T cells produce cytokines and activate CD8 + T cells and B cells. CD8 + T cells kill infected cells via ADCC. Some T cells become memory T cells, which can be quickly converted into a large number of effector T cells upon re-exposure to the same antigens. B cells recognize antigen via the B cell receptor (BCR) and can be activated with or without the help of T cells. Activated B cells differentiate into plasma cells which produce antibodies, and memory B cells which have a longer life span and help mount a rapid adaptive immune response. The part of the innate immune response is adapted from “Immunology of Adenoviral Vectors in Cancer Therapy. Molecular therapy” by Shaw AR, Suzuki M, 2019, Mol Ther Methods Clin 15:418–429 [68]

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