Intranasal Treatment with Poly(I·C) Protects Aged Mice from Lethal Respiratory Virus Infections

Zhao, Jingxian; Wohlford‐Lenane, Christine L.; Fleming, Erica; Lane, Thomas E.; McCray, Paul B.; Perlman, Stanley

doi:10.1128/jvi.01410-12

Cited by 131 publications

(154 citation statements)

References 37 publications

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“…Whether PRR reprogramming helps to resolve viral infection in vivo is still unclear. Mice preconditioned with poly(I:C) have decreased viral titers and reduced mortality when challenged with influenza virus (35). Although much of this effect may be attributed to the welldescribed "antiviral state" established by the action of type I IFNs (36, 37), we suggest that PRR reprogramming and in particular enhanced TLR7 signaling and reinforced Th1 responses may also contribute to viral clearance.…”

Section: Discussionmentioning

confidence: 79%

TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection

Hotz

Roetzer

Huber

et al. 2015

The Journal of Immunology

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Innate immune recognition of RNA is key for the initiation of immunity in response to viral infection. Although the factors controlling the detection of viral RNA by innate immune receptors in host cells are increasingly well understood, little is known about the dynamic changes in signaling after the initial triggering of these receptors. In this study, we report that preconditioning with the synthetic dsRNA polyinosinic-polycytidylic acid [poly(I:C)], a mimetic of viral RNA, rapidly reprograms murine APCs by simultaneously augmenting sensitivity of endosomal TLRs and inhibiting activation of RIG-I–like receptors (RLRs) in an IFN-β–dependent manner. These changes in receptor sensitivity were also seen in vivo after treatment of mice with poly(I:C). Mechanistically, the increased sensitivity of the TLR pathway was associated with elevated MAPK and NF-κB activity. The RLR response was inhibited downstream of TANK-binding kinase-1, resulting in decreased IFN regulatory factor 3 phosphorylation. Reprogramming of pattern-recognition receptor signaling also occurred after viral infection, because infection of host cells with Sendai virus or their exposure to supernatant from virus-infected cells induced the same changes in TLR and RLR sensitivity as poly(I:C). Thus, innate recognition of viral infection critically modifies responses to pattern-recognition receptor stimulation. These dynamic adaptations to infection may reinforce antiviral immunity and at the same time serve to limit pathological inflammation.

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Section: Discussionmentioning

confidence: 79%

TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection

Hotz

Roetzer

Huber

et al. 2015

The Journal of Immunology

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“…However, we found that the transcriptional response to flagellin was not affected during the first 2 weeks following IAV challenge, indicating that TLR5 signaling is unaffected. Respiratory administration of a TLR3 agonist or a combination of TLR2/6 and TLR9 agonists was shown to trigger protective antiviral responses (41,46). Therefore, combining antibiotics with one or more TLR agonists may constitute a unique strategy for combatting viral and bacterial respiratory coinfections.…”

Section: Discussionmentioning

confidence: 99%

A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated Pneumococcal Mouse Infections

Porte

Fougeron

Muñoz‐Wolf

et al. 2015

Antimicrob Agents Chemother

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g Prophylactic intranasal administration of the Toll-like receptor 5 (TLR5) agonist flagellin protects mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might improve the therapeutic index of antibiotics for the treatment of Streptococcus pneumoniae respiratory infections in mice. Intranasal administration of flagellin was combined with either oral administration of amoxicillin or intraperitoneal injection of trimethoprim-sulfamethoxazole to treat S. pneumoniae-infected animals. Compared with standalone treatments, the combination of antibiotic and flagellin resulted in a lower bacterial load in the lungs and greater protection against S. pneumoniae dissemination and was associated with an early increase in neutrophil infiltration in the airways. The antibiotic-flagellin combination treatment was, however, not associated with any exacerbation of inflammation. Moreover, combination treatment was more efficacious than standalone antibiotic treatments in the context of post-influenza virus pneumococcal infection. Lastly, TLR5 signaling was shown to be mandatory for the efficacy of the combined antibacterial therapy. This report is the first to show that combining antibiotic treatment with the stimulation of mucosal innate immunity is a potent antibacterial strategy against pneumonia.

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“…Consequently, these signaling events lead to the production of pro-inflammatory cytokines and type I IFNs [102,105,107]. In addition, poly I:C can increase the expression of co-stimulatory molecules in antigen-presenting cells (APCs), and promote Th1 immune responses in vivo [107][108][109]. Overall, the intrinsic immunostimulatory properties of poly I:C make it an attractive compound to be use in applications ranging from vaccine adjuvants to cancer immunotherapies.…”

Section: Benefitsmentioning

confidence: 99%

“…Respiratory Syndrome coronavirus (SARS-CoV) infection models [108,124]. With regards to PVM as well as RSV, an effective therapeutic approach should be both antiviral and immunomodulatory in nature [12,125].…”

Section: Immunomodulators In the Context Of Microbial Infectionsmentioning

confidence: 99%

Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice

et al. 2016

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Respiratory syncytial virus (RSV) is the major causative agent of acute lower respiratory tract infections in infants and young children. Unfortunately, there are no licensed RSV vaccines available, and the few treatment options for high-risk individuals are either extremely costly or cause severe side effects and toxicity. Thus, the development of effective vaccines and therapeutic interventions against RSV is a preeminent public health priority.

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Intranasal Treatment with Poly(I·C) Protects Aged Mice from Lethal Respiratory Virus Infections

Cited by 131 publications

References 37 publications

TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection

TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection

A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated Pneumococcal Mouse Infections

Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice

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