Hospital-acquired infections derived from various pathogens including P. aeruginosa (Pa) require approximately $45 billion in annual medical expenses in the U.S., according to the CDC. Despite intense interest, the function of alveolar macrophages (AM) in Pa infection remains elusive. Macroautophagy (hereafter autophagy) is a conserved homeostasis mechanism by which cellular components are sequestered to autophagosomes for degradation through ubiquitination. The autophagosome machinery may contribute to the innate immunity to enhance bacterial clearance. However, it is unknown whether autophagy impacts Pa infection. Our preliminary data revealed that Pa infection can induce autophagy, and subsequently increasing bacterial degradation. We also showed that the pleiotropic Src kinase, Lyn, interacts with toll like receptors (TLRs) to boost autophagic activity In addition, we found that Atg-7 is critical for phagosome-lysosome fusion. Importantly, starvation increases AM phagocytosis of Pa and blocking autophagy by autophagy inhibitor 3-methyladenine (3MA) decreased phagocytosis and subsequent bacterial clearance. Thus, we hypothesize that Pa-induced autophagy augments host defense by facilitating phagocytosis and bacterial degradation. Our long-term goal is to discover the key factors required for regulating host defense against Pa invasion in order to develop novel therapeutic strategies. The objective of this proposal is to examine the physiological significance of Lyn/Atg-7 modulated phagocytosis with KO mice and to delineate the underlying molecular mechanisms using biochemical and whole animal imaging approaches.
Aim 1 : Define the functional role of Atg-7 in Pseudomonas pulmonary infection. Our working hypothesis is that atg-7 is required for protection against Pa infection.
Aim 2 : Evaluate the impact of autophagy on phagocytosis in pulmonary bacterial infection utilizing a mouse model and primary mouse AM. Based on our finding that Pa infection can induce autophagy and reducing bacterial burdens in AM, our working hypothesis is that Pa-induced autophagy augments macrophage phagocytosis.
Aim 3 : Determine the role of TLR-2, Lyn, and Atg-7 in autophagosome formation and phagolysosome fusion in host response against bacteria. Thus, our working hypothesis is that TLR-2, Lyn, and Atg-7 are key elements for delivery of bacteria to lysosomes for degradation. These proposed studies will reveal a novel mechanism for AM to eradicate bacteria and suggest novel therapeutic targets.
Hospital-acquired infections impose $45 billion in annual medical expenses in the U.S., according to the CDC and Pseudomonas aeruginosa (Pa) is the fourth most commonly-isolated nosocomial bacterium. Using novel mouse models and whole animal imaging, studying novel roles of autophagy (cell self-eating) in bacterial pathogenesis will substantially advance our understanding of the function of alveolar macrophages (AM) in host defense against microbes. This application will ultimately reveal new therapeutic targets for controlling Pa and potentially other Gram-negative bacteria.
|Lv, Jiajia; Su, Wen; Yu, Qianying et al. (2018) Heme oxygenase-1 protects airway epithelium against apoptosis by targeting the proinflammatory NLRP3-RXR axis in asthma. J Biol Chem 293:18454-18465|
|Wang, Kui; Zhang, Tao; Lei, Yunlong et al. (2018) Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux. Autophagy 14:269-282|
|Chin, Willy; Zhong, Guansheng; Pu, Qinqin et al. (2018) A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset. Nat Commun 9:917|
|Ye, Yan; Lin, Ping; Zhang, Weidong et al. (2017) DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia. J Immunol 198:2844-2853|
|Wang, Xing; Yang, Xiaoqiong; Li, Yin et al. (2017) Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma. EBioMedicine 15:137-149|
|Wang, Junyi; Liu, Xiaoyu; Wang, Hui et al. (2017) Allergen specific immunotherapy enhanced defense against bacteria via TGF-?1-induced CYP27B1 in asthma. Oncotarget 8:68681-68695|
|Pu, Qinqin; Gan, Changpei; Li, Rongpeng et al. (2017) Atg7 Deficiency Intensifies Inflammasome Activation and Pyroptosis in Pseudomonas Sepsis. J Immunol 198:3205-3213|
|Zhang, Li Q; Van Haandel, Leon; Xiong, Min et al. (2017) Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase. Cell Death Dis 8:e2705|
|Zhang, Hang; Wang, Yuxi; Wu, Yangping et al. (2017) Therapeutic potential of an anti-HER2 single chain antibody-DM1 conjugates for the treatment of HER2-positive cancer. Signal Transduct Target Ther 2:17015|
|Peng, Ruchao; Xu, Ying; Zhu, Tengfei et al. (2017) Alternate binding modes of anti-CRISPR viral suppressors AcrF1/2 to Csy surveillance complex revealed by cryo-EM structures. Cell Res 27:853-864|
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