Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model.

Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy. Therefore, we studied the in vivo kinetics, and the antiviral and protective properties of a novel candidate for RSV disease treatment. The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection. At doses of 0.25-10 mg · kg(-1), TMC353121 significantly reduced viral load, bronchoalveolar lavage cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 h of infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.

Gastrointestinal nematode infection interferes with experimental allergic airway inflammation but not atopic dermatitis.

BACKGROUND: Some helminth infections are negatively associated with the prevalence of allergic disorders, arguing for a modulation of allergic reactions by the parasites, depending on the worm species, intensity and phase of infection and the type of disease. OBJECTIVE: The aim of this study was to analyse the influence of a chronic infection with the gastrointestinal nematode Heligmosomoides polygyrus, in a murine model of allergic airway disease and of atopic dermatitis (AD), respectively. METHODS: Mice were infected with H. polygyrus and systemically sensitized with the model allergen ovalbumin. Subsequently, the animals were challenged with the allergen either via the airways for induction of airway disease, or via skin patches for induction of dermatitis. RESULTS: Mice concomitantly infected with H. polygyrus showed diminished eosinophil and lymphocyte recruitment into the lungs and decreased allergen-specific IgE levels when compared with sensitized and airway challenged controls. In addition, animals showed a trend towards reduced airway hyper-reactivity. In contrast, no significant differences in the severity of eczematous skin lesions were observed between infected and control animals in the AD model. Although H. polygyrus infection reduced CD8+ and CD4+ T-cell infiltration into the skin and production of allergen-specific IgE, mast cell recruitment was significantly increased in worm-infected mice in the dermatitis model. The worm infection was associated with significantly elevated numbers of Foxp3+ regulatory T cells (Treg) in peribronchial lymph nodes in H. polygyrus-infected sensitized and airway challenged mice. In contrast, Treg cells were basically absent in eczematous skin and their number was not increased in skin-draining lymph nodes of mice with experimental dermatitis. CONCLUSION: Infection with the gastrointestinal nematode used in our study leads to significant inhibition of mucosa-associated but not cutaneous allergic reactions, pointing to a site specificity of the immunomodulation exerted by helminths. This finding might be an important aspect for future considerations of helminths for treatment of allergic diseases.