This proposal describes a 5-year training program to develop an academic career in Clinical Pathology and Microbiology. The proposed research will investigate the mucosal inflammatory response to bacterial iron metabolism. In response to diverse bacteria, the respiratory mucosa secretes siderocalin (lipocalin2), a small protein that binds the bacterial iron scavenging molecule enterobactin. Siderocalin sequesters iron from bacteria, and can prevent replication of enterobactin-dependent bacteria. In cell culture,1 siderocalin bound to enterobactin causes release of the chemokine IL-8, suggesting it has additional pro-inflammatory effects. This research plan will test the hypothesis that siderocalin mediates a mucosal inflammatory response, based on the iron-status of its bound enterobactin, through the followingaims: 1) Determine if siderocalin mediates a mucosal inflammatory response to bacteria in vivo. The PI will use animal models of nasal colonization and pneumonia,siderocalin knockout mice and isogenic Klebisiella pneumoniae enterobactin mutants to measure the effects of siderocalin on bacterial growth, chemokine production and neutrophil recriutment. 2) Identify the cellular components required for chemokine release in response to siderocalin in vitro. The PI will use a cell culture model to determine the requirement for the siderocalin receptor and chemokine regulatory proteins to respond to siderocalin. The principal investigator, Michael Bachman M.D. Ph.D., has completed his residency in Clinical Pathology at the Hospital of the Universityof Pennsylvania. He is expanding his reseach skills to include innate immunity to bacterial pathogens and focusing his career on medical microbiology. His advisor is Jeffrey Weiser M.D., an expert in the host response to bacterial colonization. To harness additional expertise, he has established a scientific advisory committee composed of Robert Wilson M.D. Ph.D.(human iron metabolism), David Artis Ph.D. (mucosal immunity) and Michael May (signal transduction). The faculty and facilities make the University of Pennsylvania an ideal environment in which to complete this training program.

Public Health Relevance

Our mucosal membranes provide the first barrier to bacterial infection, a crucial function especially important in immunocompromised and critically ill patients, and this proposal will study the protein siderocalin that inhibits bacterial growth. By understanding the mechanism of siderocalin function, we can potentially develop novel therapeutics to enhance mucosal immunity or inhibit bacterial strategies that thwart it.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM085612-05
Application #
8258806
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Somers, Scott D
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$126,495
Indirect Cost
$9,370
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Holden, Victoria I; Lenio, Steven; Kuick, Rork et al. (2014) Bacterial siderophores that evade or overwhelm lipocalin 2 induce hypoxia inducible factor 1? and proinflammatory cytokine secretion in cultured respiratory epithelial cells. Infect Immun 82:3826-36
Bachman, Michael A; Oyler, Jennifer E; Burns, Samuel H et al. (2011) Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2. Infect Immun 79:3309-16
Bachman, Michael A; Miller, Virginia L; Weiser, Jeffrey N (2009) Mucosal lipocalin 2 has pro-inflammatory and iron-sequestering effects in response to bacterial enterobactin. PLoS Pathog 5:e1000622