Search

Chlamydia trachomatis-genital infection in women can be modeled in mice using Chlamydia muridarum. Using this model, it has been shown that the cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1α lead to irreversible tissue damage in the oviducts. In this study, we investigated the contribution of TNFα on IL-1α synthesis in infected epithelial cells. We show that C muridarum infection enhanced TNFα-induced IL-1α expression and release in a mouse epithelial cell line. In addition to IL-1α, several TNFα-induced inflammatory genes were also highly induced, and infection enhanced TNF-induced cell death. In the mouse model of genital infection, oviducts from mice lacking the TNFα receptor displayed minimal staining for IL-1α compared with wild-type oviducts. Our results suggest TNFα and IL-1α enhance each other's downstream effects resulting in a hyperinflammatory response to chlamydial infection. We propose that biologics targeting TNF-induced IL-1α synthesis could be used to mitigate tissue damage during chlamydial infection. [ABSTRACT FROM AUTHOR]

Background: Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation.Results: A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001).Conclusion: This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy. [ABSTRACT FROM AUTHOR]