Lipid-based signaling modulates DNA repair response and survival against Klebsiella pneumoniae infection in host cells and in mice.

TitleLipid-based signaling modulates DNA repair response and survival against Klebsiella pneumoniae infection in host cells and in mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsHuang H, Weaver A, Wu E, Li Y, Gao H, Fan W, Wu M
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue5
Pagination798-807
Date Published2013 Nov
Abstract

Klebsiella pneumoniae causes serious infections in the urinary tract, respiratory tract, and blood. Lipid rafts, also known as membrane microdomains, have been linked to the pathogenesis of bacterial infection. However, whether lipid rafts affect K. pneumoniae internalization into host cells remains unknown. Here, we show for the first time that K. pneumoniae was internalized into lung cells by activating lipid rafts. Disrupting lipid rafts by methyl-β-cyclodextrin inhibited pathogen internalization, impairing host defense. A deficient mutant of capsule polysaccharide (CPS) showed a higher internalization rate than a wild-type strain, indicating that CPS may inhibit bacterial entry to host cells. Furthermore, lipid rafts may affect the function of extracellular regulated kinase (ERK)-1/2, and knocking down ERK1/2 via short, interfering RNA increased apoptosis in both alveolar macrophages and epithelial cells after infection. To gain insights into bacterial pathogenesis, we evaluated the impact of lipid rafts on DNA integrity, and showed that raft aggregates also affect DNA damage and DNA repair responses (i.e., 8-oxoguanine DNA glycosylase [Ogg1]) through the regulation of reactive oxygen species. Importantly, cells overexpressing Ogg1 demonstrated reduced cytotoxicity during bacterial infection. Taken together, these results suggest that lipid rafts may modulate bacterial internalization, thereby affecting DNA damage and repair, which is critical to host defense against K. pneumoniae.

DOI10.1105/tpc.113.112417
Alternate JournalAm. J. Respir. Cell Mol. Biol.