There is a large body of evidence linking zinc deficiency and pneumonia. Zinc is an essential nutrient for both humans and bacterial pathogens, but up to one third of the world population does not consume sufficient dietary zinc. The World Health Organization has estimated that zinc deficiency contributes to up to 16% of all lower respiratory globally, and a pooled analysis of randomized studies found that zinc supplementation reduced pneumonia incidence by 41%. Zinc is important for regulating the immune system, partly through direct sensing of intracellular zinc levels by immunoregulators. Additionally, the host immune protein calprotectin sequesters zinc from bacterial pathogens, suppressing their growth and dissemination. In the United States, certain populations are at increased risk for zinc deficiency and infection by the opportunistic pathogen Acinetobacter baumannii. Because zinc acquisition is critical to A. baumannii during pneumonia pathogenesis, we reasoned that it could serve as a model for defining the molecular mechanisms by which zinc deficiency increases pneumonia susceptibility. Preliminary data from our laboratory demonstrated that zinc deficiency significantly increases mortality from A. baumannii pneumonia by 24 hours post infection. The central hypothesis of this proposal is that mortality caused by A. baumannii pneumonia in zinc deficient mice is due to altered zinc homeostasis, which causes dysregulation of the innate immune response and enhanced bacterial virulence. The experiments proposed will integrate in vitro and in vivo studies linking zinc deficiency and inflammation caused by A. baumannii infection.
In Specific Aim 1, human lung epithelial cells will be analyzed for differential responses to A. baumannii exposure based on zinc status using an innovative and high throughput mass spectrometry assay platform.
Specific Aim 2 will determine the effect of zinc nutritional status on A. baumannii pneumonia by elemental and immunological analysis of the host.
In Specific Aim 3, we propose to identify bacterial genes important for the observed enhanced mortality using a high throughput transposon sequencing strategy. This integrated approach will define molecular links between zinc deficiency and pneumonia and has the potential to significantly impact our understanding of nutritional determinants of infectious disease.

Public Health Relevance

There is a well-established epidemiological link between zinc deficiency and pneumonia. We have discovered that zinc deficient mice suffer greater mortality from pneumonia caused by the opportunistic pathogen Acinetobacter baumannii. The proposed experiments will identify molecular determinants of this link using an innovative and integrated approach and have the potential to greatly impact our understanding of the effect of nutrition on infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
3F32AI122516-02S1
Application #
9405713
Study Section
Program Officer
Ernst, Nancy Lewis
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2017-01-25
Budget End
2017-06-30
Support Year
2
Fiscal Year
2017
Total Cost
$1,400
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Independent Hospitals
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Peng, Hui; Zhang, Yixiang; Palmer, Lauren D et al. (2017) Hydrogen Sulfide and Reactive Sulfur Species Impact Proteome S-Sulfhydration and Global Virulence Regulation in Staphylococcus aureus. ACS Infect Dis 3:744-755
Kinsella, Rachel L; Lopez, Juvenal; Palmer, Lauren D et al. (2017) Defining the interaction of the protease CpaA with its type II secretion chaperone CpaB and its contribution to virulence in Acinetobacter species. J Biol Chem 292:19628-19638
Peng, Hui; Shen, Jiangchuan; Edmonds, Katherine A et al. (2017) Sulfide Homeostasis and Nitroxyl Intersect via Formation of Reactive Sulfur Species in Staphylococcus aureus. mSphere 2:
Palmer, Lauren D; Skaar, Eric P (2016) Transition Metals and Virulence in Bacteria. Annu Rev Genet 50:67-91