FimH, a TLR4 ligand, induces innate antiviral responses in the lung leading to protection against lethal influenza infection in mice

• Published in: Antiviral research Vol. 92; no. 2; pp. 346 - 355
• Main Authors: Abdul-Careem, Mohamed F., Firoz Mian, M., Gillgrass, Amy E., Chenoweth, Meghan J., Barra, Nicole G., Chan, Tiffany, Al-Garawi, Amal A., Chew, Marianne V., Yue, Geoffry, Roojen, Nico van, Xing, Zhou, Ashkar, Ali A.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.11.2011; Elsevier
• Subjects: Adhesins, Escherichia coli - administration & dosage; Adhesins, Escherichia coli - immunology; Administration, Intranasal; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Movement; Chemokine CCL5 - metabolism; Fimbriae Proteins - administration & dosage; Fimbriae Proteins - immunology; FimH; Human viral diseases; Immunity, Innate - drug effects; Infectious diseases; Influenza; Influenza A virus; Influenza A virus - immunology; Influenza A virus - pathogenicity; Innate immunity; Interleukin-12 - secretion; Lung - pathology; Lung - virology; Macrophages, Alveolar - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils - immunology; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - prevention & control; Pharmacology. Drug treatments; Survival Analysis; TLR4; Toll-Like Receptor 4 - administration & dosage; Toll-Like Receptor 4 - immunology; Tumor Necrosis Factor-alpha - secretion; Viral diseases; Viral diseases of the respiratory system and ent viral diseases; Innate immunity; Lung pathology; TLR4; Influenza; FimH; Toll like receptor 4; Ligand; Lung; Rodentia; Natural immunity; Infection; Vertebrata; Mammalia; Mouse; Viral disease; Animal; Antiviral; Protection
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2011.09.004

► Local delivery of FimH provides innate antiviral protection against influenza. ► Innate antiviral activity of FimH is TLR4 dependent. ► Alveolar macrophages play a role in the FimH-mediated antiviral responses. ► Delivery of FimH into lung induces production of pro-inflammatory cytokines. Fimbriae H protein (FimH) is a novel TLR4 ligand that has been shown to stimulate the innate immune system and elicits protective responses against bacterial and viral infections. Here, we evaluated the protective role of local delivery of FimH against influenza A infection in a mouse model. We show that intranasal delivery of FimH prior to lethal challenge with influenza A virus, resulted in decreased morbidity and mortality in wild-type, but not TLR4 −/−, mice. Importantly, FimH was able to reduce the early viral burden in the lung leading to minimal cell infiltration into the airway lumen and reduced pulmonary pathology following infection in wild type mice compared to TLR4 −/− mice. Local delivery of FimH to C57BL/6, not TLR4 −/−, mice in a prophylactic manner increased the IL-12 and RANTES responses as well as neutrophil recruitment into the airway lumen. These effects correlate to the course of influenza infection. The FimH-mediated antiviral response against influenza virus appears to be partially dependent on alveolar macrophages. The antiviral effects are likely mediated by the innate mediators (TNF-α, IL-12 or RANTES) and/or by activation of a feedback inhibition loop to curtail the pulmonary inflammation possibly be the potential mechanisms involved in FimH-mediated protection. FimH thus holds promise to be a possible prophylactic mean of control against influenza viral infection.