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Title: Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epitehlial cells and in mice

Author
item WU, MIN - University Of North Dakota
item HUANG, HUANG - University Of North Dakota
item ZHANG, WEIDONG - University Of North Dakota
item KANNAN, SHIBICHAKRAVART - University Of North Dakota
item WEAVER, ANDREW - University Of North Dakota
item MCKIBBEN, MOLYNDA - University Of North Dakota
item HERINGTON, DANIELLE - University Of North Dakota
item Zeng, Huawei
item GAO, HONGWEI - Harvard Medical School

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/2010
Publication Date: 1/7/2011
Citation: Wu, M., Huang, H., Zhang, W., Kannan, S.H., Weaver, A., Mckibben, M., Herington, D., Zeng, H., Gao, H. 2011. Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epitehlial cells and in mice. Infection and Immunity. 79(1):75-87.

Interpretive Summary: Host DNA damage and DNA repair response to bacterial infections and its significance are not fully understood. Here, we demonstrate that infection by Gram-negative bacterium P. aeruginosa significantly altered the expression and enzymatic activity of base excision DNA repair protein OGG1 in lung epithelial cells. Down-regulation of OGG1 with siRNA strategy resulted in severe DNA damage and cell death. In addition, OGG1 knockout mice infected by P. aeruginosa exhibited increased lung injury with higher activities of myeloperoxidase and lipid peroxidation. An interaction between OGG1 and CSB was identified during infection, indicating that a synergy between these two DNA repair pathways is required for the repair of damaged DNA. Our studies indicate that DNA damage responses by certain DNA repair proteins, along with other signaling systems (e.g., Akt), play a critical role in host defense against P. aeruginosa, and may be promising targets for the treatment of Gram-negative bacterial infection. Thus, the elucidation of the mechanisms by which the interaction can lead to a better understanding of the nature of DNA damage. The information will be useful for scientists and health-care professionals who are interested in the prevention of bacterial infection.

Technical Abstract: Host DNA damage and DNA repair response to bacterial infections and its significance are not fully understood. Here, we demonstrate that infection by Gram-negative bacterium P. aeruginosa significantly altered the expression and enzymatic activity of base excision DNA repair protein OGG1 in lung epithelial cells. Down-regulation of OGG1 with siRNA strategy resulted in severe DNA damage and cell death. In addition, OGG1 knockout mice infected by P. aeruginosa exhibited increased lung injury with higher activities of myeloperoxidase and lipid peroxidation. Furthermore, acetylation of OGG1 correlates with host responses to bacterial genotoxicity as mutations of OGG1 acetylation sites increased nuclear excision DNA repair protein CSB expression. An interaction between OGG1 and CSB was identified during infection, indicating that a synergy between these two DNA repair pathways is required for the repair of damaged DNA. This synergy may be critical for maintaining homeostasis in severe infection cases. ExoS, a major virulence factor belonging to type 3 secretion system exoenzymes, was found to induce activities of DNA repair protein OGG1 and ERK1/2, whereas siRNA inhibition of ERK1/2 decreased cell proliferation in an Akt dependent manner. Together, our studies indicate that DNA damage responses by certain DNA repair proteins, along with other signaling systems (e.g., Akt), play a concerted role in host defense against P. aeruginosa, and may be promising targets for the treatment of Gram-negative bacterial infection.