Expert Opin Ther Targets. 2017 Apr;21(4):415-425. doi: 10.1080/14728222.2017.1299128. Epub 2017 Mar 1.
Implications of Toll-like receptors in Ebola infection.
Saghazadeh A1,2, Rezaei N1,2,3,4. Abstract
The
potential roles of toll-like receptors (TLRs) in immunopathogenesis of
Ebola virus disease should be unraveled to provoke possible prophylactic
or therapeutic implications of TLRs for EVD. Areas covered: The Ebola
virus (EBOV)
infection virtually paralyses all the main mechanisms responsible for
induction of type I interferon (IFN-I) response.
To summarize, EBOV infection interferes with
: a) the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway that is mediated by TLR3 and TLR4 signaling;
b) the interferon regulatory factor 7 (IRF7) pathway that is stimulated by TLR7 and TLR9;
c) the intracellular signaling that is induced by retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs); and
d) the autocrine/paracrine feedback loop that is mediated by the IFN-stimulated gene factor 3 (ISGF3) complex.
Upon infection with EBOV infection, TLR4 plays a key role in production of proinflammatory mediators.
Expert opinion: It is theoretically possible that use of TLRs 3, 4, 7, and 9 agonists would be beneficial to improve the IFN-I response, despite their systemic side effects.
Also, antagonist of TLR4 can be utilized to prevent production of proinflammatory cytokines.
Additionally, it is highly recommended to design future investigations aimed at determining if the utilization of IFN-I would be beneficial for prophylactic/therapeutic programs of Ebola.
KEYWORDS: Ebola virus; Toll-like receptor; interferon PMID: 28281905DOI:10.1080/14728222.2017.1299128
(2)https://www.ncbi.nlm.nih.gov/pubmed/25142601
Based on the observations in this study, therapeutic strategies that disrupt or circumvent VP35 function would be expected to increase both innate and adaptive immune responses to EBOV infection, thereby facilitating control and clearance of the virus. Because VP35 mutants lacking dsRNA-binding activity are impaired in the suppression of RLR-mediated activation of MDDCs, therapeutic approaches designed to block this function deserve attention. Because VP35 only partly impaired DC responses to TLRs, the stimulation of non-RLR pathways of DC activation should also be explored as strategies to enhance immunity to EBOV infection in vivo.
To summarize, EBOV infection interferes with
: a) the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway that is mediated by TLR3 and TLR4 signaling;
b) the interferon regulatory factor 7 (IRF7) pathway that is stimulated by TLR7 and TLR9;
c) the intracellular signaling that is induced by retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs); and
d) the autocrine/paracrine feedback loop that is mediated by the IFN-stimulated gene factor 3 (ISGF3) complex.
Upon infection with EBOV infection, TLR4 plays a key role in production of proinflammatory mediators.
Expert opinion: It is theoretically possible that use of TLRs 3, 4, 7, and 9 agonists would be beneficial to improve the IFN-I response, despite their systemic side effects.
Also, antagonist of TLR4 can be utilized to prevent production of proinflammatory cytokines.
Additionally, it is highly recommended to design future investigations aimed at determining if the utilization of IFN-I would be beneficial for prophylactic/therapeutic programs of Ebola.
KEYWORDS: Ebola virus; Toll-like receptor; interferon PMID: 28281905DOI:10.1080/14728222.2017.1299128
(2)https://www.ncbi.nlm.nih.gov/pubmed/25142601
Based on the observations in this study, therapeutic strategies that disrupt or circumvent VP35 function would be expected to increase both innate and adaptive immune responses to EBOV infection, thereby facilitating control and clearance of the virus. Because VP35 mutants lacking dsRNA-binding activity are impaired in the suppression of RLR-mediated activation of MDDCs, therapeutic approaches designed to block this function deserve attention. Because VP35 only partly impaired DC responses to TLRs, the stimulation of non-RLR pathways of DC activation should also be explored as strategies to enhance immunity to EBOV infection in vivo.
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