TLR4 and MyD88 control protection and pulmonary granulocytic recruitment in a murine intranasal RSV immunization and challenge model

Cyr, Sonya; Angers, Isabelle; Guillot, Loïc; Stoica-Popescu, Ioana; Lussier, Michèle; Qureshi, Salman T.; Burt, David S.; Ward, Brian J.

doi:10.1016/j.vaccine.2008.10.073

Cited by 34 publications

(21 citation statements)

References 56 publications

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“…This, as in our adult challenge studies, was not associated with enhanced pathology. These findings are similar to those from studies of TLR ligand administration, shown to influence RSV disease by neutrophil recruitment without inducing pathology (25). The enhanced virus clearance observed in mice primed with BPZE1 may possibly be caused by enhancement of neutrophil recruitment because neutrophils may have antiviral actions by NET formation or oxidative killing (26); alternatively, enhanced Th17 responses could increase antiviral effects by activation of NK cells (27) or by direct antiviral effects of Th17-polarized CD4 T-cell effector cells (28).…”

Section: Discussionsupporting

confidence: 88%

Attenuated Bordetella pertussis Vaccine Protects against Respiratory Syncytial Virus Disease via an IL-17–Dependent Mechanism

Schnoeller

Roux

Sawant

et al. 2014

Am J Respir Crit Care Med

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Rationale: We attenuated virulent Bordetella pertussis by genetically eliminating or detoxifying three major toxins. This strain, named BPZE1, is being developed as a possible live nasal vaccine for the prevention of whooping cough. It is immunogenic and safe when given intranasally in adult volunteers.Objectives: Before testing in human infants, we wished to examine the potential effect of BPZE1 on a common pediatric infection (respiratory syncytial virus [RSV]) in a preclinical model.Methods: BPZE1 was administered before or after RSV administration in adult or neonatal mice. Pathogen replication, inflammation, immune cell recruitment, and cytokine responses were measured.Measurements and Main Results: BPZE1 alone did not cause overt disease, but induced efflux of neutrophils into the airway lumen and production of IL-10 and IL-17 by mucosal CD4 1 T cells. Given intranasally before RSV infection, BPZE1 markedly attenuated RSV, preventing weight loss, reducing viral load, and attenuating lung cell recruitment. Given neonatally, BPZE1 also protected against RSV-induced weight loss even through to adulthood. Furthermore, it markedly increased IL-17 production by CD4 1 T cells and natural killer cells and recruited regulatory cells and neutrophils after virus challenge. Administration of anti-IL-17 antibodies ablated the protective effect of BPZE1 on RSV disease.Conclusions: Rather than enhancing RSV disease, BPZE1 protected against viral infection, modified viral responses, and enhanced natural mucosal resistance. Prevention of RSV infection by BPZE1 seems in part to be caused by induction of IL-17. Clinical trial registered with www.clinicaltrials.gov (NCT 01188512).

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Section: Discussionsupporting

confidence: 88%

Attenuated Bordetella pertussis Vaccine Protects against Respiratory Syncytial Virus Disease via an IL-17–Dependent Mechanism

Schnoeller

Roux

Sawant

et al. 2014

Am J Respir Crit Care Med

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“…Nasal application of Protollin on its own also inhibited allergic airway disease in a TLR4- dependent manner, suggesting that LPS is the active component of the adjuvant in this model. Protollin's protective effects in another murine model, as a component of an intranasal respiratory syncytial virus vaccine, were also mediated by TLR4-MyD88 signaling and not TLR2 (53). Interestingly, the N. meningitidis outer membrane vesicle vaccine, which is related in composition to Protollin, has also been shown to depend on TLR4 and not TLR2 activation (54).…”

Section: Discussionmentioning

confidence: 96%

ICOS-Expressing CD4 T Cells Induced via TLR4 in the Nasal Mucosa Are Capable of Inhibiting Experimental Allergic Asthma

Shalaby

Nakada

et al. 2012

The Journal of Immunology

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Modulation of adaptive immune responses via the innate immune pattern recognition receptors, such as the TLRs, is an emerging strategy for vaccine development. We investigated whether nasal rather than intrapulmonary application of Protollin, a mucosal adjuvant composed of TLR2 and TLR4 ligands, is sufficient to elicit protection against murine allergic lower airway disease. Wild-type, Tlr2−/−, or Tlr4−/− BALB/c mice were sensitized to a birch pollen allergen extract (BPEx), then received either intranasal or intrapulmonary administrations of Protollin or Protollin admixed with BPEx, followed by consecutive daily BPEx challenges. Nasal application of Protollin or Protollin admixed with BPEx was sufficient to inhibit allergic lower airway disease with minimal collateral lung inflammation. Inhibition was dependent on TLR4 and was associated with the induction of ICOS in cells of the nasal mucosa and on both CD4+Foxp3+ and CD4+Foxp3− T cells of the draining lymph nodes (LNs), as well as their recruitment to the lungs. Adoptive transfer of cervical LN CD4+ICOS+, but not CD4+ICOS−, cells inhibited BPEx-induced airway hyperresponsiveness and bronchoalveolar lavage eosinophilia. Thus, our data indicate that expansion of resident ICOS-expressing CD4+ T cells of the cervical LNs by nasal mucosal TLR4 stimulation may inhibit the development of allergic lower airway disease in mice.

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“…TLR4 was first implicated in RSV infections (6, 35), and while initially controversial (36), numerous studies have identified a clear connection between TLR4 and RSV clearance (6, 35, 37, 38) as well as a link involving TLR4 polymorphisms and severe RSV-induced disease in infants (9, 39–41). The ability of RSV F protein to bind and induce activation of TLR4 suggests that even the initial binding of RSV to the cell surface may provide an early innate activation signal that is important to sensing the infection.…”

Section: Discussionmentioning

confidence: 99%

Respiratory Virus-Induced TLR7 Activation Controls IL-17–Associated Increased Mucus via IL-23 Regulation

Lukacs

Smit

Mukherjee

et al. 2010

The Journal of Immunology

104

110

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The response to respiratory syncytial virus (RSV), negative strand ssRNA virus, depends upon the ability to recognize specific pathogen-associated targets. In the current study, the role of TLR7 that recognizes ssRNA was examined. Using TLR7−/− mice, we found that the response to RSV infection in the lung was more pathogenic as assessed by significant increases in inflammation and mucus production. Although there appeared to be no effect of TLR7 deficiency on type I IFN, the pathology was associated with an alteration in T cell responses with increases in mucogenic cytokines IL-4, IL-13, and IL-17. Examination of dendritic cells from TLR7−/− animals indicated a preferential activation of IL-23 (a Th17-promoting cytokine) and a decrease in IL-12 production. Neutralization of IL-17 in the TLR7−/− mice resulted in a significant decrease in the mucogenic response in the lungs of the RSV-infected mice. Thus, without TLR7-mediated responses, an altered immune environment ensued with a significant effect on airway epithelial cell remodeling and goblet cell hyper/metaplasia, leading to increased mucus production.

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TLR4 and MyD88 control protection and pulmonary granulocytic recruitment in a murine intranasal RSV immunization and challenge model

Cited by 34 publications

References 56 publications

Attenuated Bordetella pertussis Vaccine Protects against Respiratory Syncytial Virus Disease via an IL-17–Dependent Mechanism

Attenuated Bordetella pertussis Vaccine Protects against Respiratory Syncytial Virus Disease via an IL-17–Dependent Mechanism

ICOS-Expressing CD4 T Cells Induced via TLR4 in the Nasal Mucosa Are Capable of Inhibiting Experimental Allergic Asthma

Respiratory Virus-Induced TLR7 Activation Controls IL-17–Associated Increased Mucus via IL-23 Regulation

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