Helicobacter pylori remains a major public health threat, as half of the world's population is infected. Infection with the pathogen is the primary rsk factor for developing gastric cancer, the third leading cause of cancer death worldwide. Macrophages elicit a highly inflammatory, yet futile immune response to H. pylori, and thereby contribute directly to gastric carcinogenesis. I have determined that macrophages can utilize epidermal growth factor receptor (EGFR) signaling, a well-studied pathway in epithelial cells, but previously unsuspected to be of significance in macrophages. My preliminary data indicate that H. pylori infection is sufficient to induce EGFR phosphorylation and that EGFR signaling plays a major and global role in macrophage activation, polarization and function, all of which are crucial steps in the response to a pathogen. Inhibition of EGFR transactivation results in the downregulation of several key genes, including interleukin (IL)-1, tumor necrosis factor (TNF)-a and IL-10. Moreover, inhibiting pEGFR significantly impairs the ability of macrophages to produce nitric oxide, a potent antimicrobial molecule. I will determine the mechanism by which H. pylori induces EGFR signaling in macrophages. Additionally, I will elucidate the downstream targets of EGFR signaling and the effects that inhibition of EGFR activation has on a wide variety of macrophage functions, including polarization, cytokine/chemokine production, phagocytosis, antimicrobial effector production and interactions with T-cells. Using a mouse model with myeloid-specific knockout of EGFR, I will investigate the in vivo effects of EGFR signaling on H. pylori immunopathogenesis. Additionally, I will utilize tissue samples from human cohorts in Colombia and Honduras to assess the involvement of EGFR signaling in macrophages in human disease. The proposed studies will provide fundamental insights into intracellular macrophage signaling and a better understanding of H. pylori pathogenesis. My findings in macrophages in the H. pylori model are potentially applicable to general macrophage function in response to a wide variety of pathogens, opening a new direction of research within the macrophage field. Furthermore, this proposal seeks to ascertain the efficacy of targeting macrophage EGFR signaling for therapeutic intervention in inflammation-driven diseases and in gastric cancer development. This project will be an ideal training vehicle for my plan of continuing in the field of host-pathogen interactions in an academic postdoctoral fellowship. Hypothesis: EGFR activation and signaling has a novel and previously unsuspected role in regulating macrophage activation and function in response to H. pylori.
Aim 1 : Define the mechanism by which H. pylori infection induces EGFR transactivation.
Aim 2 : Determine the role of EGFR signaling in macrophage activation, polarization and function.
Aim 3 : Determine the function of EGFR signaling in macrophages on H. pylori pathogenesis in vivo.
Despite decades of research, Helicobacter pylori remains a significant human pathogen, causing inflammation of the stomach lining, and stomach cancer, the third leading cause of cancer death worldwide. Antimicrobial therapy is not uniformly effective against infection, the resulting chronic inflammation is highly carcinogenic, and host factors that contribute to gastric cancer risk remain poorly understood. The goals of this study are to define the role of a particular cellular signaling pathway (epidermal growth factor receptor signaling) in macrophages (a type of immune cell) in response to Helicobacter pylori, in order to create more targeted therapies against the chronic inflammation that leads to the carcinogenic potential of this pathogen.
|Hardbower, Dana M; Asim, Mohammad; Luis, Paula B et al. (2017) Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc Natl Acad Sci U S A 114:E751-E760|
|Hardbower, D M; Coburn, L A; Asim, M et al. (2017) EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis. Oncogene 36:3807-3819|
|Hardbower, Dana M; Singh, Kshipra; Asim, Mohammad et al. (2016) EGFR regulates macrophage activation and function in bacterial infection. J Clin Invest 126:3296-312|
|Singh, Kshipra; Al-Greene, Nicole T; Verriere, Thomas G et al. (2016) The L-Arginine Transporter Solute Carrier Family 7 Member 2 Mediates the Immunopathogenesis of Attaching and Effacing Bacteria. PLoS Pathog 12:e1005984|
|Hardbower, Dana M; Asim, Mohammad; Murray-Stewart, Tracy et al. (2016) Arginase 2 deletion leads to enhanced M1 macrophage activation and upregulated polyamine metabolism in response to Helicobacter pylori infection. Amino Acids 48:2375-88|