Hospital-acquired infections due to various pathogens including P. aeruginosa (Pa) impose huge financial burdens in the USA. Development of effective therapeutics for infection has been hampered due to limited knowledge in infection targets. Studying the molecular mechanisms of alveolar macrophages (AM) in fighting Pa infection may help discover novel therapeutic approaches. Aautophagy is a mechanism by which cellular components are sequestered to autophagosomes for degradation through ubiquitination. We recently revealed that Pa infection can induce autophagy, and subsequently increasing bacterial degradation. Toll like receptors (TLRs) are implied in linking autophagy with macrophage phagocytosis. Interestingly, our preliminary data indicate that Lyn, interacting with TLR-2, plays a critical function in facilitating phagocytosis and bactericidal activity. Moreover, Lyn may also interact with Atg-7 during Pa infection. Finally, autophagy inhibitor 3-methyladenine (3MA) decreased phagocytosis and subsequent bacterial clearance by AM. Herein, we hypothesize that autophagy enhances phagocytic function, increases bacterial clearance, and lowers inflammatory responses. The objective of this proposal is to examine the physiological significance of autophagy in Lyn-Atg7- modulated phagocytosis in knockout (KO) mice, whose inflammatory responses may be suppressed leading to less tissue injury. Our long-term goal is to identify the mechanisms of AM defense against Pa invasion in order to design novel strategies to treat this infection. The rationale is that execution of this research will define autophagy as a novel defense mechanism against Pa infection, thus suggesting new therapeutic targets. With the strong basis of scientific data and other resources available, we are well positioned to test the following specific aims.
Specific Aim 1 : Dissect the effects of autophagy on Pa phagocytosis efficiency. We hypothesize that autophagy will increase bacterial clearance by influencing phagocytic function. Mice and primary AM cells will be used to study the role of autophagy in phagocytic cup formation and bacterial clearance.
Specific Aim 2 : Study the activity of Lyn in initiating and executing autophagic pathway. We hypothesize that Lyn, by transmitting TLR2 signals, is a key regulator in Pa-induced autophagy. Activation of this signaling pathway is expected to increase the formation and maturation of autophagosomes in a newly identified immunity mechanism to combat invading Pa in the host.
Specific Aim 3 : Identify the role of Atg-7 in alleviating inflammation in mice. We hypothesize that autophagy can control the inflammatory process, thereby limiting tissue damage of infected mice. Using a novel animal imaging that includes novel luminescent reagents, we will distinguish early inflammatory responses from late ones.

Public Health Relevance

Hospital-acquired infections boast huge annual medical expenses in the USA and Pseudomonas aeruginosa (Pa) is the fourth most commonly-isolated hospital pathogen. In the past 10 years a number of studies have advanced our knowledge; however, the treatment of Pa remains a daunting challenge due to the increasing emergence of antibiotics resistance strains. As a novel mechanism we pioneered in this field, we will study novel roles of autophagy in bacterial pathogenesis, which may substantially advance our understanding of the function of alveolar macrophages (AM) in host defense against Pa. This study will ultimately reveal new therapeutic targets for controlling Pa and perhaps many other bacterial pathogens.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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University of North Dakota
Grand Forks
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Jondle, Christopher N; Gupta, Kuldeep; Mishra, Bibhuti B et al. (2018) Klebsiella pneumoniae infection of murine neutrophils impairs their efferocytic clearance by modulating cell death machinery. PLoS Pathog 14:e1007338
Savage, Christina R; Jutras, Brandon L; Bestor, Aaron et al. (2018) Borrelia burgdorferi SpoVG DNA- and RNA-Binding Protein Modulates the Physiology of the Lyme Disease Spirochete. J Bacteriol 200:
Sun, Yuyang; Schaar, Anne; Sukumaran, Pramod et al. (2018) TGF?-induced epithelial-to-mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression. Mol Carcinog 57:752-761
Tripathi, Jitendra Kumar; Sharma, Atul; Sukumaran, Pramod et al. (2018) Oxidant sensor cation channel TRPM2 regulates neutrophil extracellular trap formation and protects against pneumoseptic bacterial infection. FASEB J :fj201800605
Basson, Marc D; Wang, Qinggang; Chaturvedi, Lakshmi S et al. (2018) Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation. Cell Physiol Biochem 48:1274-1290
Greenmyer, Jacob R; Gaultney, Robert A; Brissette, Catherine A et al. (2018) Primary Human Microglia Are Phagocytically Active and Respond to Borrelia burgdorferi With Upregulation of Chemokines and Cytokines. Front Microbiol 9:811
Sun, Yuyang; Sukumaran, Pramod; Selvaraj, Senthil et al. (2018) TRPM2 Promotes Neurotoxin MPP+/MPTP-Induced Cell Death. Mol Neurobiol 55:409-420
Bhattacharya, Atrayee; Kumar, Janani; Hermanson, Kole et al. (2018) The calcium channel proteins ORAI3 and STIM1 mediate TGF-? induced Snai1 expression. Oncotarget 9:29468-29483
Quenum Zangbede, Fredice O; Chauhan, Arun; Sharma, Jyotika et al. (2018) Galectin-3 in M2 Macrophages Plays a Protective Role in Resolution of Neuropathology in Brain Parasitic Infection by Regulating Neutrophil Turnover. J Neurosci 38:6737-6750
Chauhan, Arun; Sun, Yuyang; Sukumaran, Pramod et al. (2018) M1 Macrophage Polarization Is Dependent on TRPC1-Mediated Calcium Entry. iScience 8:85-102

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