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Title: The role of Caspase-1 in a murine model of influenza pneumonitis, and studies on cell death inhibitors in Vitro
Keywords: Caspase-1, Influenza virus, Inflammation, Lung, Cell death
Issue Date: 11-Jan-2011
Source: LIEW AUDREY-ANN (2011-01-11). The role of Caspase-1 in a murine model of influenza pneumonitis, and studies on cell death inhibitors in Vitro. ScholarBank@NUS Repository.
Abstract: Influenza is a highly contagious respiratory disease that poses significant threat to human health worldwide and exacts considerable economic burden. Lung pathology observed during influenza infection is due to direct damage resulting from viral replication and bystander damage caused by overly exuberant antiviral immune mechanisms. Virus-induced pro-inflammatory interleukin-1ß (IL-1ß) and IL-18 are processed via caspase-1 in the inflammasome. This study investigated the role of caspase-1 in influenza virus-associated pulmonary pathology and inflammation using a mouse model of influenza pneumonitis. Caspase-1-deficient (Casp1-/-) and wild-type C57BL/6 mice were infected with 500 plaque-forming units of influenza A/Puerto Rico/8/34 (H1N1) virus. Increased virus titres were observed in the lungs of Casp1-/- mice at day 7 post-infection compared to wild-type animals, suggesting that Casp1-/- mice are more susceptible to infection. Histopathologic analysis, based on lung injury scores, of Casp1-/- mice at day 7 post-infection exhibited increased intra-alveolar fibrin deposition, implying augmented alveolar damage. Casp1-/- mice also displayed increased cellular recruitment in the lungs. The pulmonary infiltration was predominantly neutrophilic in the bronchoalveolar lavage fluid (BALF) of Casp1-/- mice at days 3 and 6 post-infection. Lower levels of IL-1ß protein were detected in the lungs of Casp1-/- mice, but higher levels of IFN-¿, MCP-1, MIP-1a, MIP-1ß, RANTES were found in the lung airways that correlated with the increased inflammation. A higher average number of TUNEL-positive lung cells per field and elevated protein concentration were observed in BALF of Casp1-/- mice, indicating a greater degree of lung damage in the caspase-1-deficient mice. Interestingly, 2 of the 10 infected Casp1-/- mice exhibited brain inflammation that was absent in wild-type counterparts. Up-regulation of caspase-1 expression by RT-PCR and Western blot analyses was also observed in infected wild-type mice and in infected RAW264.7 murine macrophages. Transcriptomic analysis of infected lungs revealed that caspase-4 gene expression increased to a lower extent in infected Casp1-/- mice than the wild-type group. The gene expression microarray also revealed that genes differentially expressed in the infected Casp1-/- mice suggest a greater severity of influenza pathogenesis in the lungs of these mice. This study provided a thorough histopathological analysis of the lung with quantitative scoring as well as analysis of other organs, namely the brain and heart. Cell death assays were performed on the lung section and BALF cells which substantiated the increased lung damage observed in Casp1-/- mice. The microarray analysis unveiled genes with differential expression which may influence the outcome of influenza A pathogenesis in caspase-1-deficiency. Our study suggests a protective role of caspase-1 in the regulation of inflammatory host response in combating influenza infection and reveals the molecular pathways that underpin its functional mechanisms.
Appears in Collections:Master's Theses (Open)

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