Prophylactic intranasal administration of a TLR2 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model

Proud, Pamela C.; Tsitoura, Daphne C.; Watson, Robert J.; Chua, Brendon Y.; Aram, Marilyn; Bewley, Kevin R.; Cavell, Breeze E.; Cobb, Rebecca; Dowall, Stuart; Fotheringham, Susan; Ho, Catherine M. K.; Lucas, Vanessa; Ngabo, Didier; Rayner, Emma; Ryan, Kathryn A.; Slack, Gillian S.; Thomas, Stephen R.; Wand, Nadina; Yeates, Paul; Demaison, Christophe; Jackson, David C.; Bartlett, Nathan W.; Mercuri, Francesco; Carroll, Miles W.

doi:10.1101/2020.09.25.309914

Cited by 5 publications

(5 citation statements)

References 39 publications

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“…Furthermore, it has not escaped our attention that INNA-X treatment can be implemented as a multi-dosing regimen to extend and provide continuous protection throughout the course of an outbreak. Of note and highly relevant to COVID19, our recent studies have since demonstrated its protective efficacy against SARS-CoV-2 in a ferret model (46) establishing proof-of-concept that this strategy can be applied in the face of rapidly spreading pandemic viruses to protect immunologically naïve global populations.…”

Section: Discussionmentioning

confidence: 85%

TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs

Deliyannis¹,

Wong²,

McQuilten³

et al. 2021

JCI Insight

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The impact of respiratory virus infections on global health is felt not just during a pandemic but for many, endemic seasonal infections pose an equal and ongoing risk of severe disease. Moreover, vaccines and antiviral drugs are not always effective or available for many respiratory viruses. We investigated how induction of effective and appropriate antigen independent innate immunity in the upper airways can prevent spread of respiratory virus infection to the vulnerable lower airways. Activation of toll-like receptor-2 (TLR2), when restricted to the nasal turbinates results in prompt induction of innate immune-driven anti-viral responses through action of cytokines, chemokines and cellular activity in the upper but not the lower airways. We define how nasal epithelial cells and recruitment of macrophages work in concert and play pivotal roles to limit progression of influenza virus to the lungs and sustain protection for up to seven days. These results reveal underlying mechanisms of how control of viral infection in the upper airways can occur and also support the implementation of strategies that can activate TLR2 in nasal passages to provide rapid protection, especially for at-risk populations, against severe respiratory infection when vaccines and antiviral drugs are not always effective or available.

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Section: Discussionmentioning

confidence: 85%

TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs

Deliyannis¹,

Wong²,

McQuilten³

et al. 2021

JCI Insight

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“…20,22,28 TLR agonists could also be used as prophylactic drugs for SARS-CoV-2. Proud et al 29 revealed that prophylactic administration of TLR2/6 agonist reduces SARS-CoV-2 transmission and provides protection against COVID-19. Stimulation of TLR2 leads to activation of the innate immune response, suppression of excessive inflammation and tissue damage, as well as promotion of the integrity of local epithelial barrier function.…”

Section: Tlrs In Sars-cov-2mentioning

confidence: 99%

Role of Toll‐like receptors in the pathogenesis of COVID‐19

Khanmohammadi

Rezaei

2021

Journal of Medical Virology

285

262

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Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a pandemic since March 2020. The exact pathogenesis of SARS-CoV-2 and the role of each component of the innate and adaptive immune system is still unknown. However, available data from other coronavirus families, such as SARS-CoV and the Middle East respiratory syndrome and also new findings could be useful for a better understanding of SARS-CoV-2. Toll-like receptors (TLR) play an important role in recognition of viral particles and activation of the innate immune system. Activation of TLR pathways leads to secretion of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α, as well as type 1 interferon. Different TLRs, like TLR2, TLR3, TLR4, TLR6, TLR7, TLR8, and TLR9 are potentially important in COVID-19 infection. It is also worth mentioning that we should bear in mind both the beneficial and harmful effects of TLR in confronting COVID-19 infection. TLRs could be a potential target in controlling the infection in the early stages of disease and production of vaccine against SARS-CoV-2.

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“…Several PRRs on DCs, including TLR2 [22,42,29], TLR4 [41,21], and DC-SIGN [3,32], have already been demonstrated to bind SARS-CoV-2 proteins. Here we dramatically found that DC-SIGN might give rise to antibody levels but suppress IgG/Ab ratio, which was opposite to DC maturation and function.…”

Section: Discussionmentioning

confidence: 99%

Phenotypes and Functions of Dendritic Cells in SARS-CoV-2 Vaccine-derived Humoral Immunity

Chen

et al. 2022

Preprint

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DCs regulate humoral immunity against SARS-CoV-2 by regulating CD4 + T cell activation, but the relations between DC phenotypes and functions and anti-RBD antibodies are unclear. We conducted this observational study in Huashan Hospital using a third 6.5U BBIBP-CorV or 25 µg ZF2001 administered at an interval of 4 to 8 months following the previous two doses in healthy adults. anti-RBD response and neutralizing titers against SARS-CoV-2 and VOCs were examined. DC maturation markers and pattern recognition receptors and cytokines produced by DC were measured, and DC function was tested in mixed lymphocyte reaction(MLR). Mean anti-RBD Ab and IgG rose from 22.08 and 9.17 on D0 to 4704.18 and 798.11 on D14(BAU/ml). Meanwhile, the surrogate virus neutralization test(sVNT) elevated from 17.15 on D0 to 2538.83 on D14. The expression of DC maturation markers on D3 and MLR were negatively correlated to sVNT, anti-RBD antibody, and IgG titers on D14(Spearman r=-0.558~-0.326) and D28(Spearman r=-0.615~-0.397), but positively correlated to IgG/Ab ratio(Spearman r = 0.249 ~ 0.509). DC function in activating T cells was also negatively related to anti-RBD antibody titer on D28(r=-0.532~-0.453, p = 0.015 ~ 0.035), and positively correlated with the proportion of anti-RBD IgG in Ab(r = 0.490 ~ 0.561, p = 0.010 ~ 0.032). DC-SIGN level showed a relation to antibody titer and IgG proportion opposite to DC maturation and function and was negatively related to the level of IL-10 produced by DCs. Our research suggested that DCs controlled CD4 + T cells in differentiating into regular T cells, and DC-SIGN might restrain T regular cells by suppressing IL-10 production of DC in anti-SARS-CoV-2 vaccination.

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Prophylactic intranasal administration of a TLR2 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model

Cited by 5 publications

References 39 publications

TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs

TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs

Role of Toll‐like receptors in the pathogenesis of COVID‐19

Phenotypes and Functions of Dendritic Cells in SARS-CoV-2 Vaccine-derived Humoral Immunity

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