Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats

Hammerbeck, David M.; Burleson, Gary R.; Schuller, Craig J.; Vasilakos, John P.; Tomai, Mark A.; Egging, Elaine A.; Cochran, Felicia R.; Woulfe, Susan L.; Miller, Richard L.

doi:10.1016/j.antiviral.2006.07.011

Cited by 70 publications

(59 citation statements)

References 57 publications

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“…reported pretreatment with TLR9 and TLR3 agonists upregulated the TLRs within hours and protected mice against lethal influenza (A/H1N1, A/H3N2, A/H5N1) infections for 7–14 days. Prophylactic TLR7/8 or TLR7 agonist administration also resulted in virus inhibition and improved mice survival 11, 17. Interestingly, the virus inhibitory effects of TLR agonists were found to be superior to exogenously administered interferons16, 17 and synergistic with oseltamivir 15.…”

Section: Discussionmentioning

confidence: 99%

“…TLR9 activation in DCs strongly induces the release of type‐1 IFNs and pro‐inflammatory cytokines and upregulates the co‐stimulatory molecules (e.g., CD80/86);3, 14 TLR7/8 activation induces IFNs, the pro‐inflammatory IL‐6, TNF‐α, CCL2/MCP‐1, and CXCL8/IL‐8 and promotes DC maturation;3, 11, 17 TLR3 in epithelial cells causes tissue inflammation in influenza pneumonia through IL‐6, TNF‐α, and CXCL8/IL‐8 induction and effector cell recruitment 3, 7, 8. Limited available reports had described upregulations of the “viral‐sensing” TLRs in association with the inflammatory cytokines in patients with severe A/H1N1pdm09 influenza 27, 28, 29.…”

Section: Discussionmentioning

confidence: 99%

“…Prophylactic TLR7/8 or TLR7 agonist administration also resulted in virus inhibition and improved mice survival 11, 17. Interestingly, the virus inhibitory effects of TLR agonists were found to be superior to exogenously administered interferons16, 17 and synergistic with oseltamivir 15. Our findings in naturally occurring influenza thus provide strong support to further investigate this novel approach of TLR targeting and activation as a means of preventive intervention against influenza in humans (e.g., as pre‐ or post‐exposure prophylaxis) 4, 15…”

Section: Discussionmentioning

confidence: 99%

“…TLR's active role in cytokine induction was supported by our ex vivo experiments, which showed significant differences in cellular cytokine responses between patients with influenza and controls upon TLR‐specific ligand stimulation (e.g., CpG DNA‐TLR9 and imiquimod‐TLR7; the resultant response pattern governed by the ligand tested, cell type studied, and disease stage at the time of sampling/“immune exhaustion”) and a dynamic change in their responsiveness during clinical recovery 20, 32. Perpetuating, uncontrolled pro‐inflammatory cytokine responses can lead to immunopathological damage in severe influenza (Data S1); and further stimulation of TLRs in a more advanced disease stage may exacerbate tissue inflammation 5, 6, 7, 8, 11, 17, 20, 22, 29. Whether TLR blockade alone can reduce inflammation is uncertain as compensatory mechanisms might exist 4, 5, 15.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies have also revealed an additional cytosolic system of retinoic acid‐inducible gene‐1 (RIG‐1)‐like receptor proteins (RLRs) that detect influenza viral RNAs, contributing to the innate responses 3, 7, 10, 13. Recently, data from animal studies have further shown that targeting the TLRs (with agonists) may rapidly upregulate the innate immunity to provide broad‐range, virus strain non‐specific protection against lethal influenza challenge 4, 11, 14, 15, 16, 17. However, our understanding on TLR's importance in natural influenza is very limited because of lack of clinical data.…”

Section: Introductionmentioning

confidence: 99%

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Role of human Toll‐like receptors in naturally occurring influenza A infections

Lee

Wong

Hui

et al. 2013

Influenza Resp Viruses

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BackgroundWe investigated the roles of Toll‐like receptors (TLRs) in naturally occurring influenza.MethodsA prospective, case – control study was conducted. Adults hospitalized with virologically confirmed influenza A infections (onset <48 hours, before treatment) were compared with age‐/gender‐matched controls. TLRs (2, 3, 4, 7, 8, 9) expression in monocytes and dendritic cells (DCs – total, myeloid, plasmacytoid) was quantitated using flow cytometry. Gene expression of RLRs (RIG‐1, MDA‐5) was evaluated using real‐time PCR. Concomitant signaling molecules expression, plasma cytokine/chemokine concentrations, and respiratory tract viral loads were measured. PBMCs were cultured and stimulated ex vivo with TLR‐specific ligands for cytokine responses.ResultsForty two patients with influenza (24 A/H3N2, 18 A/H1N1pdm09) and 20 controls were studied. Patients' mean age was 68 ± 16 years; 81% had respiratory/cardiovascular complications. There were increased cellular expressions of TLR9, TLR8, TLR3, and TLR7 during influenza; TLR2 and TLR4 were suppressed. Results were similar for both virus strains. Higher TLR expression levels at presentation significantly correlated with lower viral loads (Spearman's rho: −0·46 to −0·69 for TLR9, TLR8, and TLR3; P‐values <0·05). Multivariate regression models (adjusted for age, comorbidity, disease severity, time from onset) confirmed their independent associations. Increased signaling molecules (phospho‐MAPKs, IκB) and inflammatory cytokines (IL‐6, sTNFR‐1, CCL2/MCP‐1; CXCL10/IP‐10, IFN‐γ) correlated with increased TLR expression. RLRs were upregulated simultaneously. PBMCs of patients with influenza showed significant, dynamic changes in their cytokine responses upon TLR stimulation, compared with controls.ConclusionsOur results suggest that TLRs play an important role in early, innate viral inhibition in naturally occurring influenza. Inflammatory cytokine responses are concomitantly induced. These findings support investigation of TLR targeting as a novel intervention approach for prophylaxis against influenza.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Role of human Toll‐like receptors in naturally occurring influenza A infections

Lee

Wong

Hui

et al. 2013

Influenza Resp Viruses

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Animal Models of Host Resistance

Burleson¹,

Burleson²

2008

Immunotoxicology Strategies for Pharmaceutical Safety Assessment

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Induction of adaptive immunity by flagellin does not require robust activation of innate immunity

et al. 2009

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The ability of TLR agonists to promote adaptive immune responses is attributed to their ability to robustly activate innate immunity. However, it has been observed that, for adjuvants in actual use in research and vaccination, TLR signaling is dispensable for generating humoral immunity. Here, we examined the role of TLR5 and MyD88 in promoting innate and humoral immunity to flagellin using a prime/boost immunization regimen. We observed that eliminating TLR5 greatly reduced flagellin-induced cytokine production, except for IL-18, and ablated DC maturation but did not significantly impact flagellin's ability to promote humoral immunity. Elimination of MyD88, which will ablate signaling through TLR and IL-1b/IL-18 generated by Nod-like receptors, reduced, but did not eliminate flagellin's promotion of humoral immunity. In contrast, loss of the innate immune receptor for profilinlike protein (PLP), TLR11, greatly reduced the ability of PLP to elicit humoral immunity. Together, these results indicate that, firstly, the degree of innate immune activation induced by TLR agonists may be in great excess of that needed to promote humoral immunity and, secondly, there is considerable redundancy in mechanisms that promote the humoral immune response upon innate immune recognition of flagellin. Thus, it should be possible to design innate immune activators that are highly effective vaccine adjuvants yet avoid the adverse events associated with systemic TLR activation.Key words: Adjuvant . Cytokines . DC . Profilin-like protein . TLR Introduction TLR-mediated recognition of structural components of microbial pathogens plays a key role in the initiation of host defense. Specifically, these germ-line-encoded PRR recognize and initiate immune responses to a wide variety of microbial patterns, including those of bacteria, viruses, parasites, nucleic acids, carbohydrates, and lipids [1][2][3][4]. TLR agonists are classified into three broad categories such as nucleic acids (TLR 3,7,8,9), lipids/lipopeptides (TLR 4, 1/2, 2/6), and protein (TLR 5,11). Of particular importance to this study, TLR5 recognizes the bacterial protein flagellin [5], in its soluble/monomeric form, whereas TLR11 recognizes profilin-like protein (PLP), made by Toxoplasma gondii [6]. Activation of most TLR, including TLR5 and Eur. J. Immunol. 2009. 39: 359-371 DOI 10.1002 HIGHLIGHTS 359 Frontline TLR11, by their cognate ligands results in rapid nuclear translocation of the transcription factor NF-kB and, consequently, synthesis and secretion of a panel of pro-inflammatory cytokines. Another class of PRR thought to play an important role in innate immunity is the Nod-like receptors (NLR), which are expressed in the cytosol. Of particular relevance to this study, two NLR proteins, Ipaf and Naip5, have been reported to signal in response to flagellin that attains an intracellular location [7][8][9][10]. In contrast to TLR, the primary consequence of Ipaf signaling is not to induce transcription or protein synthesis but rather to activate caspase-1, which resul...

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Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats

Cited by 70 publications

References 57 publications

Role of human Toll‐like receptors in naturally occurring influenza A infections

Role of human Toll‐like receptors in naturally occurring influenza A infections

Animal Models of Host Resistance

Induction of adaptive immunity by flagellin does not require robust activation of innate immunity

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